5-ht2a agonists for use in treatment of depression

ABSTRACT

The present invention relates to agonists of the 5-HT2A serotonin receptors and their medical uses. In one aspect the invention relates to 5-HT2A agonists of formula (I). In second aspect, the invention relates to selective 5-HT2A agonists of formula (II). In another aspect, the invention relates to mixed 5-HT2A/5-HT2C agonists of formula (III). In yet another aspect, the invention relates to 5-HT2A agonists for use in the treatment of a depressive disorder, more particular a 5-HT2A agonist for the use in the treatment of treatment-resistant depression.

FIELD OF THE INVENTION

The present invention relates to agonists of the 5-HT_(2A) serotoninreceptors. In a one aspect, the invention relates to 5-HT_(2A) agonists.In another aspect, the invention relates to selective 5-HT_(2A)agonists. In yet another aspect, the invention relates to mixed5-HT_(2A)/5-HT_(2C) agonists. In yet another aspect, the inventionrelates to 5-HT_(2A) agonists for use as medicament in particular foruse in the treatment of a depressive disorder, more particular a5-HT_(2A) agonist for the use in the treatment of treatment-resistantdepression.

BACKGROUND OF THE INVENTION

Depression was for a long time considered an illness of the soul but itis currently viewed as a disorder of the brain. A shift in paradigmbegan more than 50 years ago, following the discovery that biogenicamines, notably norepinephrine (also called noradrenaline (NA)) andserotonin (5-hydroxytryptamine, 5-HT), act as neurotransmitters in thebrain. The monoamine hypothesis of depression was first proposed,referring essentially to the monoamines (NA, 5-HT and dopamine), andlater the possible role of serotonin was emphasized. Serotonin isinvolved in and regulates diverse biological functions in the brain,such as e.g. mood, emotion and sleep. Thus, the serotonergic system andserotonin receptors have been investigated for several decades inrelation to treatment of depression as well as in relation to otherpsychiatric disorders. In its original formulation, the 5-HT hypothesisfor depression postulated a deficit in brain 5-HT levels as a primarycause, reversed by antidepressants, which would restore normal functionin depressed patients.

The current “first-line” therapies for major depressive disorder (MDD)can be grouped into three classes: the selective serotonin reuptakeinhibitors (SSRIs), the serotonin and norepinephrine reuptake inhibitors(SNRIs), and the norepinephrine-dopamine reuptake inhibitors (NDRIs).These reuptake inhibitors show varying degrees of selectivity for thethree transporters mediating uptake of the three monoamines, with SSRIshaving negligible affinities for the norepinephrine and dopaminetransporters. The primary medications used in the treatment ofdepression today are the SSRIs that largely have replaced oldergenerations of antidepressants, such as tricyclic antidepressants (TCAs)and monoamine oxidase inhibitors. Several SSRIs exist, such assertraline (Zoloft, Lustral), escitalopram (Lexapro, Cipralex),fluoxetine (Prozac), paroxetine (Seroxat) and citalopram (Celexa). TheSSRIs are believed to exert their effects via an increase in theextracellular level of serotonin by limiting its reuptake into thepresynaptic cell, thereby increasing the level of serotonin in thesynaptic cleft available to bind to and activate presynaptic andpostsynaptic serotonin receptors. While the modern classes ofantidepressants offer superior tolerability and safety over oldermedications such as the TCAs, presently there is no universallyeffective pharmacologic treatment for MDD. Hence, effective diseasemanagement requires careful attention and continuous assessment ofmedication response and management of side effects. Thus, the SSRI classof medications is not without drawbacks, the most notable of these beingthe slow on-set of the antidepressant effects of the drugs(weeks-to-months) and the fact that approximately one half of patientsare “non-responders”, i.e. do not respond significantly to the SSRI atall. Moreover, administration of SSRIs is associated with adverseeffects such as nausea, weight gain and reduced libido. Nevertheless,the significant safety and tolerability advantages of SSRIs compared tothe TCAs and their modest but real tolerability advantages compared tothe SNRIs justify considering this class of medications first whenselecting an antidepressant for a mild-to-moderately severe episode ofMDD.

Several addition therapies with non-antidepressant medication have beeninvestigated within depression. These addition therapies have been shownto increase the effectiveness of the antidepressant and to be effectivein people with treatment-resistant depression in some cases. Suchaddition therapies include benzodiazepines, atypical antipsychotics, andstimulants such as amphetamines and methylphenidate (Ritalin). As anexample, the atypical antipsychotic aripiprazole has been approved bythe US Food and Drug Administration as adjunct to antidepressants forthe treatment of MDD. Furthermore, the NMDA receptor antagonist ketaminehas shown effect as a rapid-acting antidepressant fortreatment-resistant depression. However, several of these therapies comewith serious side effects and in the case of the stimulants also havethe potential of drug abuse. Thus, there is still an unmet need forfurther development of new medications for the treatment of depression,in particular new medications effective for use in treatment-resistantdepression.

Recent research efforts have shown that classical psychedelics may beuseful for the treatment of psychiatric disorders, e.g. majordepression, severe depression, treatment-resistant depression, alcoholdependence, alcohol use disorder, nicotine dependence, cocaine-relateddisorders, heroin dependence, obsessive compulsive disorder, eatingdisorders, general anxiety, death-related anxiety in terminal cancerpatients, PTSD, Alzheimer's disease, mild cognitive impairment,distress, grief, migraine headache, post traumatic headache, clusterheadache, Parkinson's disease, and psychosis.^(1, 2) The psychedelicsare a class of drugs whose primary action is to trigger psychedelicexperiences via serotonin receptor agonism, producing thought andvisual/auditory changes and an altered state of consciousness. Classicalpsychedelics include mescaline (the active constituent of the peyotecactus), lysergic acid diethylamide (LSD), psilocybin (the activeconstituent of psilocybin mushrooms commonly known as “magic mushrooms”)and N,N-dimethyltryptamine (DMT) (the active component in ayahuasca).Most classical psychedelic drugs fall into one of three families: thetryptamines, phenethylamines or ergolines. Although ergolines constitutetheir own group, they are in fact both tryptamines and phenethylamines.

The classical psychedelics exhibit polypharmacology, i.e. mediateeffects on numerous neurotransmitter receptors. For example, LSD acts asa full agonist/partial agonist at a plethora of monoaminergic receptors,and psilocin (active metabolite of psilocybin) acts as agonist/partialagonist on numerous 5-HT receptors. However, the rapid antidepressanteffects of these classical psychedelics have primarily been ascribed totheir activation of 5-HT_(2A) receptors.³

The serotonin receptor family comprises at least 14 different receptorsubtypes divided into subfamilies (5-HT₁ to 5-HT₇). The 5-HT₂ receptorfamily is composed by the subtypes 5-HT_(2A), 5-HT_(2B) and 5-HT_(2C).As mentioned above, 5-HT_(2A) is thought to be the primary targetmediating the antidepressant effects of classical psychedelics. Incontrast, 5-HT_(2B) is mainly expressed in peripheral tissues, and it isknown to mediate cardiac side effects of non-selective serotoninreceptor agonists. Thus, research efforts aimed at exploring thepotential of 5-HT_(2A) as a putative target in depression have focusedon developing 5-HT_(2A)/5-HT_(2C) agonists that do not target 5-HT_(2B),in particular 5-HT_(2A) selective agonists that target neither 5-HT_(2B)nor 5-HT_(2C). However, this has proven difficult, since 5-HT_(2B) and5-HT_(2C) are closely homologous to 5-HT_(2A). Furthermore, discovery oftruly selective agonists requires determination of agonist potency andefficacy in functional assays, as selectivity in terms of bindingaffinities (K_(i) or IC₅₀) determined in radioligand competition bindingassays may not translate into the same selectivity in functional assays.One disclosure of agonists that displays 5-HT_(2A)-over-5-HT_(2C)selectivity has been reported in J. Pharmacol Exp. Ther. 2017, 361,441-453, using the 4-(2-(benzylamino)ethyl)-2,5-dimethoxybenzonitrilescaffold. As an example, the compound 25CN—NBOH exhibited a functionalselectivity for 5-HT_(2A) over 5-HT_(2C) (20-fold or 127-fold) whenmeasured in two fluorescence-based Ca²⁺ imaging assays. However, thesecompounds are generally less suited in terms of drug-like properties,and they are metabolically unstable and/or toxic.⁴⁻⁵ Another disclosureof agonists that display 5-HT_(2A)-over-5-HT_(2C) selectivity has beenreported in ACS Chem. Neurosci. 2013, 4, 96-109, using2,5-diaryl-piperidine scaffolds, 4-aryl-1,2,3,4-tetrahydroisoquinolinescaffolds and 2-benzyl-6-arylpiperidine scaffolds. One of the2-benzyl-6-arylpiperidine scaffolds in the series exhibited a reasonableselectivity for 5-HT_(2A) over 5-HT_(2C) (124-fold) in terms of bindingaffinity, and the racemic mixture of the compound displayed 5-HT_(2A)agonism in a functional inositol phosphate (IP) assay. However, thecompound was not tested functionally at 5-HT_(2C), and its5-HT_(2A)-over-5-HT_(2C) selectivity in the binding assays does notnecessarily translate into a similar degree of selectivity in afunctional assay.

The 2-benzyl-6-arylpiperidine scaffolds 8a and 8b reported in ACS Chem.Neurosci. 2013, 4, 96-109, showed moderate 5-HT_(2A)-over-5-HT_(2C)selectivity in terms of binding affinity (13-fold and 27-fold,respectively) and were further characterized by the inventors due tosome structural similarity with the scaffolds of the present invention.The inventors have demonstrated that only compound 8a evoked significantagonist responses at 5-HT_(2A) in the functional Ca²⁺/Fluo-4 assay andin the functional inositol phosphate (IP) assay at concentrations up to50 M and 100 M, respectively, and that compound 8b exhibited no agonistresponse in these assays at all (see table 1a and 4). Thus, compound 8bis not a 5-HT_(2A) agonist. Furthermore, compound 8a showed selectivitytowards 5-HT₂, and 5-HT_(2B) over 5-HT_(2A), in the IP assay and onlyslight selectivity towards 5-HT_(2A) over 5-HT_(2C) in the Ca²⁺/Fluo-4assay (see table 1a and 4). Furthermore, both of these scaffolds mayalso suffer from the same drawbacks in terms of being metabolicallyunstable and/or toxic as the4-(2-(benzylamino)ethyl)-2,5-dimethoxybenzonitrile scaffold as they alsocomprises an N-benzylated amine.

Since the effects of psilocin and other classical psychedelics onvarious psychiatric conditions have been proposed to arise mainly fromtheir 5-HT_(2A) agonist component, the inventors hypothesized that itmay suffice to activate these receptors alone to obtain the rapidanti-depressant effect exhibited by these drugs. The lack of selective5-HT_(2A) agonists with CNS drug-like properties has so far hampered theexploration of the therapeutic potential in such drugs. Moreover, in thelight of the diversity and complexity of depression disorders, it may behypothesized that some patient groups could benefit from a mixed5-HT_(2A)/5-HT_(2C) agonist, whereas in other patient groups, aselective 5-HT_(2A) agonist may be sufficient or even better than mixed5-HT_(2A)/5-HT_(2C) agonists. Accordingly, a first object of theinvention is to provide 5-HT_(2A) agonists. A second object of theinvention is to provide selective 5-HT_(2A) agonists that are selectiveover 5-HT_(2C) and/or 5-HT_(2B). Another object of the invention is toprovide mixed 5-HT_(2A)/5-HT_(2C) agonists. Even further, an object ofthe invention is to provide compounds for use in the treatment ofdepression, in particular for use in the treatment oftreatment-resistant depression. The inventors have surprisingly found anew class of compounds comprising a3-(2,4,5-trisubstituted-phenyl)piperidine, a3-(2,4-disubstituted-phenyl)piperidine or a3-(3,4-disubstituted-phenyl)piperidine that all act as 5-HT_(2A)agonists, wherein a subgroup (i.e. the (S)-enantiomers) of thesecompounds act as selective 5-HT_(2A) agonists (particularly in regard to5-HT_(2C) and/or 5-HT_(2B)). Further, the inventors surprisingly foundyet another class of compounds comprising a3-(2,4,5-trisubstituted-phenyl)azetidine or a3-(2,4,5-trisubstituted-phenyl)pyrrolidine that act as very potentagonists with roughly equipotent activity at 5-HT_(2A) and 5-HT_(2C).All of these compounds may be beneficial in the treatment of depression,in particular in the treatment of individuals suffering fromtreatment-resistant depression.

Thus, in a first aspect, the invention relates to 5-HT_(2A) agonistscomprising a 3-(2,4,5-trisubstituted-phenyl)piperidine, a3-(2,4-disubstituted-phenyl)piperidine or a3-(3,4-disubstituted-phenyl)piperidine.

In a second aspect, the invention relates to a subgroup (i.e. the(S)-enantiomers) of the compounds according to the first aspect, thatare selective for 5-HT_(2A) over 5-HT_(2C) and/or 5-HT_(2B). In a thirdaspect, the invention relates to 5-HT_(2A)/5-HT_(2C) agonists,preferably 5-HT_(2A)/5-HT_(2C) agonists that are selective over5-HT_(2B). Further aspects of the invention includes the compounds inthe first, second and/or third aspect for use as a medicament, inparticular for use as a medicament in the treatment of a depressivedisorder, more particular for use as a medicament in the treatment oftreatment-resistant depression.

Definitions

According to the present invention, C₁-C₅ alkyl is to be understood asunivalent groups derived from alkanes (C_(n)H_(2n+2)) by removal of ahydrogen atom from any carbon atom where n is 1-5, i.e. 1-5 carbon atomsare comprised. C₁-C₅ alkyls may be linear (—C_(n)H_(2n+1)) or branched(—C_(n)H_(2n+1)). Likewise, C₁-C₅ cycloalkyl (—C_(n)H_(2n+1)) is to beunderstood as univalent groups derived from cycloalkanes (C_(n)H_(2n))by removal of a hydrogen atom from any carbon atom where n is 3-5, i.e.3-5 carbon atoms are comprised. C_(x)-C_(y), such as C₁-C₅, generallyrefers to the total number of carbon atoms also for alkenyls andalkynyls. C₂-C₅ alkenyls and C₂-C₅ alkynyls may be linear or branched.Furthermore, C₂-C₅ alkenyls or alkynyls may contain one or morealkene(s) or alkyne(s).

According to the present invention, fluoroalkyl should be understood asan alkyl group wherein, one or more hydrogen (—H) atom(s) has/have beenreplaced by (a) fluorine (—F) atom(s). Thus, in the present context, afluoroalkyl may be fully fluorinated, mono-fluorinated or anything inbetween. As a non-limiting example, C₂-fluoroalkyl may refer to e.g.—CF₂CF₃, —CF₂CHF₂, —CF₂CH₂F, —CF₂CH₃, —CHFCF₃, —CHFCHF₂, —CHFCH₂F,—CHFCH₃, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F. As another non-limiting example,C₁-fluoroalkyl may refer to —CF₃, —CF₂H or —CFH₂. Fluoroalkenyl andfluoroalkynyl should be understood in a similar way. Flourination may besuitable to e.g. prevent sites from being metabolized.

According to aspects 1 and 3 of the present invention, a 5-HT_(2A)agonist should be understood as an agonist activating 5-HT_(2A)receptors with an EC₅₀ below 12 μM, such as below 10 μM, such as below 5μM, preferably below 3 μM, such as below 2 μM, more preferably below 1μM, even more preferably below 0.5 μM when measured in the functionalCa²⁺/Fluo-4 assay as described in the experimental section.

According to aspects 2 and 4 of the present invention, a 5-HT_(2A)selective agonist should be understood as an agonist activating5-HT_(2A) receptors with an EC₅₀ below 5 μM, such as below 3 μM,preferably below 2 μM, more preferably below 1 μM, even more preferablybelow 0.5 μM, such as below 0.25 μM, more preferably below 0.15 μM, suchas below 0.12 μM, even more preferably below 0.1 μM, such as below 90nM, most preferably below 80 nM, such as below 70 nM, when measured inthe Ca²⁺/Fluo-4 functional assay and in addition displays selectivitytowards 5-HT_(2A) over 5-HT_(2C) when measured in the functionalCa²⁺/Fluo-4 assay (as described in the experimental section) and/orselectivity towards 5-HT_(2A) over 5-HT_(2B) when measured in thefunctional inositol phosphate (IP) assay (as described in theexperimental section). The lack of significant agonist activityexhibited by a compound at the 5-HT_(2C) receptor at the concentrationranges tested in the functional Ca²⁺/Fluo-4 assay may either be theresult of very low agonist potency at the receptor, of the compoundpossessing so low agonist efficacy at the receptor that it cannot bedetected in the assay, or of the compound being a competitive antagonistand thus per definition having no agonist efficacy at the receptor. Mostpreferably, the 5-HT_(2A) selective agonists do not show any agonistactivity (efficacy) in the Ca²⁺/Fluo-4 functional assay. Thus,preferably, the selectivity for 5-HT_(2A) towards 5-HT_(2C) (i.e. EC₅₀^(5-HT2C)/EC₅₀ ^(5-HT2A)) is at least a factor of 2, such as at least afactor of 3, such as at least a factor of 4, more preferably at least afactor 5, such as at least a factor of 6, such as at least a factor of7, even more preferably at least a factor of 8, such as at least afactor of 9, yet more preferably at least a factor of 10, such as atleast a factor of 11, such as at least a factor of 12, yet morepreferably at least a factor of 20, such as at least a factor of 30,most preferably at least a factor of 100 when the 5-HT_(2A) and5-HT_(2C) EC₅₀ values are measured in the Ca²⁺/Fluo-4 functional assayas described in the experimental section. Preferably, the selective5-HT_(2A) agonists do not activate 5-HT_(2B) significantly. Therefore,preferably the selectivity towards 5-HT_(2B) (i.e. EC₅₀ ^(5-HT2B)/EC₅₀^(5-HT2A)) is at least a factor of 2, such as a factor of 3, such as afactor of 4, more preferably a factor of at least 5, such as a factor of6, such as a factor of 7, even more preferably at least a factor of 8when the 5-HT_(2A) and 5-HT_(2B) EC₅₀ values are measured in thefunctional IP assay described in the experimental section.

According to aspects 3 and 6 of the present invention, a mixed5-HT_(2A)/5-HT_(2C) agonist should be understood as an agonistactivating both 5-HT_(2A) and 5-HT_(2C) with a 5-HT_(2A) EC₅₀ valuebelow 5 μM, such as below 3 μM, such as below 2 μM, preferably below 1μM, such as below 0.5 μM, more preferably below 0.25 μM, yet morepreferably below 100 nM and a 5-HT_(2C) EC₅₀ value below 3 μM, such asbelow 2 μM, preferably below 1 μM, such as below 0.5 μM, more preferablybelow 0.25 μM, yet more preferably below 100 nM when measured in thefunctional Ca²⁺/Fluo-4 assay described in the experimental section.Preferably, the 5-HT_(2A) EC₅₀ value is below 90 nM, such below 80 nM,such as below 70 nM, more preferably below 60 nM, such as below 50 nM,even more preferably below 40 nM, such as below 30 nM, most preferablybelow 20 nM, such as below 10 nM. Preferably, the 5-HT_(2C) EC₅₀ valueis below 90 nM, such below 80 nM, preferably below 70 nM, morepreferably below 60 nM, most preferably below 50 nM. Preferably theselectivity between 5-HT_(2A) and 5-HT_(2C) (i.e. EC₅₀ ^(5-HT2C)/EC₅₀^(5-HT2A)) is less than a factor of 20, such as less than a factor of15, more preferably less than a factor of 10, such as a factor of lessthan 8, most preferably less than a factor of 7, such as a factor lessthan 6. Preferably, the mixed 5-HT_(2A)/5-HT_(2C) agonists do notactivate 5-HT_(2B). Likewise, preferably the selectivity for 5-HT_(2A)towards 5-HT_(2B) (i.e. EC₅₀ ^(5-HT2B)/EC₅₀ ^(5-HT2A)) is at least afactor of 2, such as a factor of 3, such as a factor of 4, morepreferably a factor of at least 5, such as a factor of 6, such as afactor of 7, even more preferably at least a factor of 8 when the5-HT_(2A) and 5-HT_(2B) EC₅₀ values are measured in IP assay describedin the experimental section.

The compounds according to the present invention have also shown topossess high selectivity in terms of binding affinity (lower K_(i)values) at 5-HT₂ receptors as exemplified for compound 8 compared toother monoaminergic receptors such as members of the other serotoninreceptor subfamilies (5-HT₁, 5-HT₃, 5-HT₅, 5-HT₆ and 5-HT₇), members ofthe norepinephrine receptor families (α_(1A), α_(1B), α_(1C), α_(2A),α_(2B), α_(2C)) and the dopamine receptors (D₁, D₂, D₃, D₄, D₅) (seeTable 3), when measured in the binding assays described in theexperimental section. Thus, according to the invention a 5-HT_(2A)agonist should preferably have a K_(i) value on D₁-D₅ above 1000 nM,such as above 2000 nM, preferably above 3000 nM, such as above 4000 nM,more preferably above 5000 nM, such as above 6000 nM, even morepreferably above 7000 nM, such as above 8000 nM, most preferably above9000 nM, such as above 10000 nM when measured in the dopamine receptorbinding assays described in the experimental section. Likewise,according to the invention, a 5-HT_(2A) agonist should preferably have aK_(i) on α_(1A), α_(1B) and α_(2C), above 1000 nM, such as above 2000nM, preferably above 3000 nM, such as above 4000 nM, more preferablyabove 5000 nM, such as above 6000 nM, even more preferably above 7000nM, such as above 8000 nM, most preferably above 9000 nM, such as above10000 nM and a K_(i) value on α_(2A) and α_(2B) above 200 nM, such asabove 250 nM, preferably above 300 nM, such as above 350 nM, morepreferably above 400 nM, such as above 450 nM, even more preferablyabove 500 nM, such as above 550 nM, most preferably above 550 nM, suchas above 600 nM when measured in the norepinephrine receptor bindingassays described in the experimental section. Likewise, a 5-HT_(2A)agonist should preferably have a K_(i) value on 5-HT₃ and 5-HT_(5A)above 1000 nM, such as above 2000 nM, preferably above 3000 nM, such asabove 4000 nM, more preferably above 5000 nM, such as above 6000 nM,even more preferably above 7000 nM, such as above 8000 nM, mostpreferably above 9000 nM, such as above 10000 nM and preferably a K_(i)value on 5-HT_(1A), 5-HT_(1D), 5-HT₆ and 5-HT₇ above 100 nM, such asabove 150 nM, preferably above 200 nM, such as above 250 nM, morepreferably above 300 nM when measured in the serotonin receptor bindingassay described in the experimental section.

According to the present invention treatment-resistant depression (TRD)should be understood as a depressive disorder, preferably majordepressive disorder (MDD), that cannot be treated adequately with knownantidepressants and/or psychotherapy, such that a desired clinicaloutcome can be reached (i.e. inadequate response observed). Aninadequate response should be understood as no clinical response (e.g.no improvement in depressive symptoms) or a person who does not achievefull remission of depressive symptoms.

SUMMARY OF THE INVENTION

In the first aspect the invention relates to 5-HT_(2A) agonists of thegeneral formula (I)

or a pharmaceutically acceptable salt thereof wherein:

* denotes the (R) or (S) stereoisomer or any mixture thereof;

X is selected from the group consisting of I, CN, S—(C₁-C₅ alkyl),S—(C₁-C₅ fluoroalkyl), S—(C₂-C₅ alkenyl), S—(C₂-C₅ fluoroalkenyl),S—(C₂-C₅ alkynyl), S—(C₂-C₅ fluoroalkynyl), C₂-C₅ alkyl, C₁-C₅fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅ fluoroalkenyl, C₂-C₅ alkynyl, andC₂-C₅ fluoroalkynyl;

Y¹ and Y² are independently selected from the group consisting of H, O,S, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and halogen;

R¹ is not present when Y is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

R² is not present when Y² is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

when present, R¹ and R² are independently selected from the groupconsisting of C₁-C₅ alkyl, C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅fluoroalkenyl, C₂-C₅ alkynyl, C₂-C₅ fluoroalkynyl, C₃-C₅ cycloalkyl andC₃-C₅ fluorocycloalkyl;

z denotes the number of R³ groups and is an integer with a value of 0,1, 2, 3 or 4;

R³ is/are independently selected from the group consisting of F, C₁-C₃alkyl, C₁-C₃ fluoroalkyl, C₂-C₃ alkenyl and C₁-C₃ alkynyl;

R⁴ is selected from H or CH₃;

with the proviso that at least one of Y¹ or Y² is selected as O or S.

In a second aspect, the invention relates to selective 5-HT_(2A)agonists of the general formula (II)

or a pharmaceutically acceptable salt thereof wherein:

X is selected from the group consisting of I, CN, S—(C₁-C₅ alkyl),S—(C₁-C₅ fluoroalkyl), S—(C₂-C₅ alkenyl), S—(C₂-C₅ fluoroalkenyl),S—(C₂-C₅ alkynyl), S—(C₂-C₅ fluoroalkynyl), C₂-C₅ alkyl, C₁-C₅fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅ fluoroalkenyl, C₂-C₅ alkynyl, andC₂-C₅ fluoroalkynyl;

Y¹ and Y² are independently selected from the group consisting of H, O,S, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and halogen;

R¹ is not present when Y is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

R² is not present when Y² is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

when present, R¹ and R² are independently selected from the groupconsisting of C₁-C₅ alkyl, C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅fluoroalkenyl, C₂-C₅ alkynyl, C₂-C₅ fluoroalkynyl, C₃-C₅ cycloalkyl andC₃-C₅ fluorocycloalkyl;

z denotes the number of R³ groups and is an integer with a value of 0,1, 2, 3 or 4;

R³ is/are independently selected from the group consisting of F, C₁-C₃alkyl, C₁-C₃ fluoroalkyl, C₂-C₃ alkenyl and C₂-C₃ alkynyl;

with the proviso that at least one of Y¹ or Y² is selected as O or S.

In a third aspect, the invention relates to mixed 5-HT_(2A)/5-HT_(2C)agonists of the general formula (III)

or a pharmaceutically acceptable salt thereof wherein:

X is selected from the group consisting of I, CN, S—(C₁-C₅ alkyl),S—(C₁-C₅ fluoroalkyl), S—(C₂-C₅ alkenyl), S—(C₂-C₅ fluoroalkenyl),S—(C₂-C₅ alkynyl), S—(C₂-C₅ fluoroalkynyl), C₂-C₅ alkyl, C₁-C₅fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅ fluoroalkenyl, C₂-C₅ alkynyl, andC₂-C₅ fluoroalkynyl;

Y¹ and Y² are independently selected from the group consisting of O, S,C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and halogen;

R¹ is not present when Y is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

R² is not present when Y² is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

when present, R¹ and R² are independently selected from the groupconsisting of C₁-C₅ alkyl, C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅fluoroalkenyl, C₂-C₅ alkynyl, C₂-C₅ fluoroalkynyl, C₃-C₅ cycloalkyl andC₃-C₅ fluorocycloalkyl;

* denotes the (R) or (S) stereoisomer or any mixture thereof if a chiralcenter is present;

n is an integer with a value of 1, 2, 3 or 4 to form an azetidine,pyrrolidine, piperidine or azepane ring system;

z denotes the number of R³ groups and is an integer with a value of 0,1, 2, 3 or 4;

R³ is/are independently selected from the group consisting of F, C₁-C₃alkyl, C₁-C₃ fluoroalkyl, C₂-C₃ alkenyl and C₂-C₃ alkynyl;

R⁴ is selected from H or CH₃;

with the proviso that when n=3, * denotes the (R) stereoisomer andfurther with the proviso that at least one of Y¹ or Y² is selected as Oor S.

In a fourth aspect, the invention relates to 5-HT_(2A) agonists of thegeneral formula (I) or a pharmaceutically acceptable salt thereof foruse as a medicament

wherein:

* denotes the (R) or (S) stereoisomer or any mixture thereof;

X is selected from the group consisting of F, Cl, Br, I, CN, S—(C₁-C₅alkyl), S—(C₁-C₅ fluoroalkyl), S—(C₂-C₅ alkenyl), S—(C₂-C₅fluoroalkenyl), S—(C₂-C₅ alkynyl), S—(C₂-C₅ fluoroalkynyl), C₁-C₅ alkyl,C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅ fluoroalkenyl, C₂-C₅ alkynyl,and C₂-C₅ fluoroalkynyl;

Y¹ and Y² are independently selected from the group consisting of H, O,S, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, or halogen;

R¹ is not present when Y is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

R² is not present when Y² is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

when present, R¹ and R² are independently selected from the groupconsisting of C₁-C₅ alkyl, C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅fluoroalkenyl, C₂-C₅ alkynyl, C₂-C₅ fluoroalkynyl, C₃-C₅ cycloalkyl andC₃-C₅ fluorocycloalkyl;

z denotes the number of R³ groups and is an integer with a value of 0,1, 2, 3 or 4;

R³ is/are independently selected from the group consisting of F, C₁-C₃alkyl, C₁-C₃ fluoroalkyl, C₂-C₃ alkenyl and C₂-C₃ alkynyl;

R⁴ is selected from H or CH₃;

with the proviso that at least one of Y¹ or Y² are selected as O or S.

In a fifth aspect, the invention relates to selective 5-HT_(2A) agonistsof the general formula (II) or a pharmaceutically acceptable saltthereof for use as a medicament

wherein:

X is selected from the group consisting of F, Cl, Br, I, CN, S—(C₁-C₅alkyl), S—(C₁-C₅ fluoroalkyl), S—(C₂-C₅ alkenyl), S—(C₂-C₅fluoroalkenyl), S—(C₂-C₅ alkynyl), S—(C₂-C₅ fluoroalkynyl), C₁-C₅ alkyl,C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅ fluoroalkenyl, C₂-C₅ alkynyl,and C₂-C₅ fluoroalkynyl;

Y¹ and Y² are independently selected from the group consisting of H, O,S, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and halogen;

R¹ is not present when Y¹ is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

R² is not present when Y² is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

when present, R¹ and R² are independently selected from the groupconsisting of C₁-C₅ alkyl, C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅fluoroalkenyl, C₂-C₅ alkynyl, C₂-C₅ fluoroalkynyl, C₃-C₅ cycloalkyl andC₃-C₅ fluorocycloalkyl;

z denotes the number of R³ groups and is an integer with a value of 0,1, 2, 3 or 4;

R³ is/are independently selected from the group consisting of F, C₁-C₃alkyl, C₁-C₃ fluoroalkyl, C₂-C₃ alkenyl and C₂-C₃ alkynyl;

with the proviso that at least one of Y¹ or Y² are selected as O or S.

In a sixth aspect, the invention relates to mixed 5-HT_(2A)/5-HT_(2C)agonists or a pharmaceutically acceptable salt thereof of the generalformula (III) for use as a medicament

wherein:

X is selected from the group consisting of F, Cl, Br, I, CN, S—(C₁-C₅alkyl), S—(C₁-C₅ fluoroalkyl), S—(C₂-C₅ alkenyl), S—(C₂-C₅fluoroalkenyl), S—(C₂-C₅ alkynyl), S—(C₂-C₅ fluoroalkynyl), C₁-C₅ alkyl,C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅ fluoroalkenyl, C₂-C₅ alkynyl,and C₂-C₅ fluoroalkynyl;

Y¹ and Y² are independently selected from the group consisting of H, O,S, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and halogen;

R¹ is not present when Y is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

R² is not present when Y² is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

when present, R¹ and R² are independently selected from the groupconsisting of C₁-C₅ alkyl, C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅fluoroalkenyl, C₂-C₅ alkynyl, C₂-C₅ fluoroalkynyl, C₃-C₅ cycloalkyl andC₃-C₅ fluorocycloalkyl;

* denotes the (R) or (S) stereoisomer or any mixture thereof if a chiralcenter is present;

n is an integer with a value of 1, 2, 3 or 4 to form an azetidine,pyrrolidine, piperidine or azepane ring system;

z denotes the number of R³ groups and is an integer with a value of 0,1, 2, 3 or 4;

R³ is/are independently selected from the group consisting of F, C₁-C₃alkyl, C₁-C₃ fluoroalkyl, C₂-C₃ alkenyl and C₂-C₃ alkynyl;

R⁴ is selected from H or CH₃;

with the proviso that when n=3, * denotes the (R) stereoisomer andfurther with the proviso that at least one of Y¹ or Y² is selected as Oor S.

A seventh aspect of the invention relates to a method of synthesis ofthe compounds according to any of the preceding aspects of theinvention.

An eighth aspect relates to particular medical uses of the compoundsaccording to the invention.

A ninth aspect relates to pharmaceutical compositions comprising one ormore compounds according to the invention.

The invention will now be described in more detail in the followingembodiments.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A shows the concentration-dependent responses elicited by compound8 in 5-HT_(2A)-, 5-HT_(2B)- and 5-HT_(2C)-expressing cell lines in thefunctional Ca²⁺/Fluo-4 assay when tested as agonist. FIG. 1B shows theconcentration-dependent inhibition of the 5-HT EC_(BO)-induced responsein the 5-HT_(2C)-expressing cell line in the same assay mediated bycompound 8 when tested as antagonist. The assay was performed asdescribed in the experimental section.

FIGS. 2A and 2B show the head twitch response (HTR) induced by compound8 in mice and rats, respectively. It is well-established that 5-HT_(2A)agonists elicit this characteristic HTR in rodents, and the behaviouraleffect thus represents a demonstration of CNS exposure and 5-HT_(2A)agonism in vivo.^(6, 7) FIG. 2A shows the dose-dependent increase of HTRmediated by compound 8 (subcutaneous administration) in male C57BL/6Jmice. FIG. 2B shows the dose-dependent increase of HTR mediated bycompound 8 (intraperitoneal administration) in Sprague Dawley male rats.

FIG. 3 shows the effects of compound 8 and (S)-ketamine (which belongsto another class of rapid antidepressant drugs) on immobility time ofFlinders Sensitive Line (FSL) rats in the forced swim test. The FSL is agenetic rodent model for depression, as the animals exhibit reducedappetite, reduced mobility, anhedonia and sleep abnormalities.⁸ TheFlinders Resistant Line (FRL) is a control line that exhibits none ofthese depression-like symptoms. Both compound 8 (1.5 mg/kg, i.p.) and(S)-ketamine (15 mg/kg, i.p.) reduce the immobility time compared to thevehicle-treated FSL rats one hour after intraperitoneal administration.

FIG. 4A shows the effects of compound 8 and the TCA imipramine onimmobility time of rats treated with adrenocorticotropic hormone (ACTH)in the forced swim test. Chronic administration of rats with ACTHabrogates the antidepressant effect of TCAs, such as imipramine, and itis thus a validated stress-induced rodent model of treatment-resistantdepression.⁹ FIG. 4B shows the significant antidepressant-like effect ofimipramine (15 mg/kg, i.p.) in vehicle-treated rats (positive control),which contrasts the lack of effect of the same dose of imipramine inACTH-treated rats (FIG. 4A).

FIG. 5 shows the x-ray structure of compound 59.

FIG. 6 shows the x-ray structure of compound 58.

DETAILED DESCRIPTION OF THE INVENTION

Aspect 1—5-HT_(2A) agonists of the general formula (I)

The inventors found that compounds comprising a3-(2,4,5-trisubstituted-phenyl)piperidine, a3-(2,4-disubstituted-phenyl)piperidine or a3-(3,4-disubstituted-phenyl)piperidine act as potent 5-HT_(2A) agonistsand show promising results as anti-depressants. Thus, one overallinventive concept relates to 5-HT_(2A) agonists and their use asmedicaments, preferably their use as anti-depressant medicaments,wherein the 5-HT_(2A) agonists comprise a3-(2,4,5-trisubstituted-phenyl)piperidine, a3-(2,4-disubstituted-phenyl)piperidine or a3-(3,4-disubstituted-phenyl)piperidine.

In the first aspect the invention relates to 5-HT_(2A) agonists of thegeneral formula (I)

or a pharmaceutically acceptable salt thereof wherein:

* denotes the (R) or (S) stereoisomer or any mixture thereof;

X is selected from the group consisting of I, CN, S—(C₁-C₅ alkyl),S—(C₁-C₅ fluoroalkyl), S—(C₂-C₅ alkenyl), S—(C₂-C₅ fluoroalkenyl),S—(C₂-C₅ alkynyl), S—(C₂-C₅ fluoroalkynyl), C₂-C₅ alkyl, C₁-C₅fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅ fluoroalkenyl, C₂-C₅ alkynyl, andC₂-C₅ fluoroalkynyl;

Y¹ and Y² are independently selected from the group consisting of H, O,S, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and halogen;

R¹ is not present when Y¹ is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

R² is not present when Y² is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

when present, R¹ and R² are independently selected from the groupconsisting of C₁-C₅ alkyl, C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅fluoroalkenyl, C₂-C₅ alkynyl, C₂-C₅ fluoroalkynyl, C₃-C₅ cycloalkyl orC₃-C₅ fluorocycloalkyl;

z denotes the number of R³ groups and is an integer with a value of 0,1, 2, 3 or 4;

R³ is/are independently selected from the group consisting of F, C₁-C₃alkyl, C₁-C₃ fluoroalkyl, C₂-C₃ alkenyl and C₂-C₃ alkynyl;

R⁴ is selected from H or CH₃

with the proviso that at least one of Y¹ or Y² is selected as O or S.

Substituent X

The inventors found that the substituent X in Formula (I) was importantfor the potency of the 5-HT_(2A) agonists and that X tolerated a varietyof lipophilic substituents. The skilled person is aware of a range ofsubstituents that are suitable to fulfill the role as a lipophilicsubstituent. Thus, in an embodiment of the invention, X is selected fromI, CN, S—(C₁-C₅ alkyl), S—(C₁-C₅ fluoroalkyl), C₂-C₅ alkyl, C₁-C₅fluoroalkyl. In a preferred embodiment, X is selected from I, CN,S—(C₁-C₃ alkyl), S—(C₁-C₃ fluoroalkyl), C₂-C₅ alkyl, C₁-C₅ fluoroalkyl.In a more preferred embodiment, X is selected from I, CN, S—(C₁-C₃alkyl), S—(C₁-C₃ fluoroalkyl), C₂-C₄ alkyl, C₁-C₄ fluoroalkyl. In yet amore preferred embodiment, X is selected from I, CN, S—CH₃, S—CF₃, C₂-C₃alkyl, C₁-C₃ fluoroalkyl. In an even more preferred embodiment of theinvention, X is selected from I, CF₃, CN, S—CH₃, S—CF₃. In a yet an evenmore preferred embodiment, X is selected from I, CF₃, CN, S—CH₃. In ahighly preferred embodiment, X is selected from I, CF₃, S—CH₃. In aneven more highly preferred embodiment of the invention, X is selectedfrom I or CF₃. In the most preferred embodiment of the invention, X isCF₃.

Substituents Y¹ and Y²

The inventors further found that Y¹ and Y² could be selected from H, O,S, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, or halogen with the proviso that atleast one of Y¹ or Y² are selected as O or S. It follows that when Y¹ isH, halogen, C₁-C₃ fluoroalkyl, or C₁-C₃ alkyl, R¹ is not present(deleted). Likewise, when Y² is H, halogen, C₁-C₃ fluoroalkyl, or C₁-C₃alkyl, R² is not present (deleted). In an embodiment of the invention Y¹is selected from O, S, CH₃ or halogen and Y² is selected from O, S, CH₃or halogen. In a preferred embodiment of the invention Y¹ is selectedfrom O, S, H or halogen and Y² is selected from O, S, H or halogen. Inyet a preferred embodiment Y¹ is selected from O, S, or CH₃ and Y² isselected from O, S, or CH₃. In a more preferred embodiment of theinvention Y¹ is selected from O, S or H and Y² is selected from O, S orH. In yet a more preferred embodiment Y¹ is selected from O or S and Y²is selected from O or S. In yet a preferred embodiment, Y¹ is O or S,and Y² is selected from H, halogen, O or S. In particular, the presenceof a heteroatom in Y¹ and Y² provided potent 5-HT_(2A) compounds. Thus,in an embodiment of the invention, Y¹ is O, and Y² is S. In anotherembodiment of the invention, Y¹ is S, and Y² is O. In yet anotherembodiment, Y¹ and Y² are S. In the most preferred embodiment of theinvention, Y¹ and Y² are O.

Substituent R¹ and R²

The inventors surprisingly found that the pharmacophore occupied by R¹and R² in formula (I) allowed small lipophilic substituents whilemaintaining 5-HT₂ activity and potency of the compounds. Thus, in anembodiment of the invention, R¹ and R² are independently selected fromthe group consisting of not present (R¹ not present if Y is H, C₁-C₃alkyl, C₁-C₃ fluoroalkyl, or halogen, R² not present if Y² is H, C₁-C₃alkyl, C₁-C₃ fluoroalkyl or halogen), C₁-C₅ alkyl, C₁-C₅ fluoroalkyl,C₃-C₅ cycloalkyl or C₃-C₅ fluorocycloalkyl. In a preferred embodiment ofthe invention, R¹ and R² are independently selected from the groupconsisting of C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₃-C₅ cycloalkyl or C₃-C₅fluorocycloalkyl. In yet a more preferred embodiment, R¹ and R² areindependently selected from the group consisting of C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₃-C₅ cycloalkyl. In yet an even more preferred embodimentof the invention, R¹ and R² are independently selected from the groupconsisting of C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and cyclopropyl. In aneven more preferred embodiment, R¹ and R² are independently selectedfrom the group consisting of C₁-C₃ alkyl and C₁-C₃ fluoroalkyl. In ahighly preferred embodiment, R¹ and R² are independently selected fromthe group consisting of C₁-C₂ alkyl and C₁-C₂ fluoroalkyl. In anotherhighly preferred embodiment, R¹ and R² are independently selected fromthe group consisting of C₁-C₂ alkyl. In an even more preferredembodiment, R¹ and R² are independently selected from the groupconsisting of methyl (CH₃) and trifluoromethyl (CF₃). In the mostpreferred embodiment of the invention, R¹ and R² are both methyl (CH₃).

Type of R³ substituent(s)

In an embodiment of the invention, the R³ group(s) is/are independentlyselected from the group consisting of F, C₁-C₃ alkyl and C₁-C₃fluoroalkyl. In a preferred embodiment of the invention, the R³ group(s)is/are independently selected from the group consisting of F, C₁-C₂alkyl and C₁-C₂ fluoroalkyl. In the highly preferred embodiment of theinvention, the R³ group(s) is/are independently selected from the groupconsisting of F, methyl (CH₃) and trifluoromethyl (CF₃). In the mostpreferred embodiment of the invention, the R³ group(s) is/areindependently selected from the group consisting of F and methyl (CH₃).

Number (z) of R³ Substituent(s) and Preferred Positions

The inventors further found that the carbon atoms in the piperidine ringsystem could be substituted with small lipophilic substituents (R³).Thus, according to the present invention, the one or more R³substituent(s) (if present) is/are present at any of the positions (2),(3), (4), (5) and/or (6) as shown in formula (I) below. More preferably,one or more R³ substituent(s) (if present) is/are present at any of thepositions (2), (3) and/or (6) as shown in in formula (I) below, mostpreferably at position (2) or (3) as shown in in formula (I) below. Itfollows that two R³ substituents may be present on the same position(carbon atom). The inventors found that the secondary amine (free NH) inthe piperidine ring system was highly important for maintaining highagonist activity at the 5-HT_(2A) receptor, whereas nitrogensubstituents (tertiary amines) led to a significant loss of potency at5-HT_(2A) (factor ˜80 for compound 59 (N-Et) and a factor ˜20 forcompound 61 (N-Me) compared to compound 8). In some less preferredembodiments, the piperidine may be/methylated despite the loss ofpotency in order to change other properties, e.g. ADME properties.

Thus, in an embodiment of the invention, z is 0-4 such that thepiperidine is unsubstituted or substituted with 1-4 R³ groups. In apreferred embodiment of the invention, z is 0-3 such that the piperidineis unsubstituted or substituted with 1-3 R³ groups. In a more preferredembodiment of the invention, z is 0-2 such that the piperidine isunsubstituted or substituted with 1-2 R³ groups. In an even morepreferred embodiment of the invention, z is 0-1 such that the piperidineis unsubstituted or substituted with one R³ group. In the most preferredembodiment of the invention z is O, such that no R³ substituents arepresent.

In a highly preferred embodiment of the invention, z is 0 or 1, suchthat the piperidine is unsubstituted or substituted with one R³ group, awherein the one R³ group is present in any of the positions indicated as(2), (3), (4), (5) or (6) in formula (I) above, preferably in any of thepositions indicated (2), (3) or (6) in formula (I) above, mostpreferably in the position indicated as (2) or (3) in formula (I) above.

Stereochemistry

In the first aspect, the compounds of formula (I) comprise both the (R)and (5) stereoisomers at the chiral center denoted *. The compounds maytherefore be a single stereoisomer or a mixture of the (R) and (5)stereoisomers in any ratio such as a 1:1 mixture of stereoisomers on thecenter denoted * (i.e. racemate if no R³ groups are present). It isevident to the skilled person that in case of R³ substituents on thepiperidine, one or more additional chiral centers may be present in themolecule. These other chiral centers may also be either in the (R) and(S) configuration in accordance with Cahn-Ingold-Prelog priority rules.The number of stereoisomers possible depends on the number of chiralcenters present and can be calculated as 2^(n), where n is the number ofadditional chiral centers. In the present context, the invention isintended to cover all the single stereoisomers possible as well as anymixture thereof. The stereoisomers according to the present inventionmay be separated using conventional methods in the art. Thus,diastereomers may be separated by selective crystallization, liquidcolumn chromatography, such as conventional silica gel chromatography orHigh Performance Liquid Chromatography (HPLC) (reverse andnormal-phase). Furthermore, enantiomers may be separated using chiralresolution, such as chiral HPLC, chiral SFC or by chiral derivatizingagents to form diastereomers that may be separated with any of theabove-mentioned conventional methods.

Preferred Embodiments

In a preferred embodiment of the invention, X is selected from I, CN,S—(C₁-C₃ alkyl), S—(C₁-C₃ fluoroalkyl), C₂-C₃ alkyl, C₁-C₃ fluoroalkyl;Y¹ is selected from H, O, S, CH₃ or halogen; Y² is selected from H, O,S, CH₃ or halogen. R¹ and R² are independently selected from the groupconsisting of not present (R¹ not present if Y is H, CH₃ or halogen, R²not present if Y² is H, CH₃ or halogen), C₁-C₃ alkyl, C₁-C₃ fluoroalkyl,cyclopropyl; z is 0, 1, 2 or 3; and R³ is/are independently selectedfrom F, CH₃ or CF₃; with the proviso that at least one of Y¹ or Y² areselected as O or S.

In another preferred embodiment of the invention, X is selected from I,CN, S—(C₁-C₃ alkyl), S—(C₁-C₃ fluoroalkyl), C₂-C₃ alkyl, C₁-C₃fluoroalkyl; Y¹ is selected from H, O, or S; Y² is selected from H, O,or S. R¹ and R² are independently selected from the group consisting ofnot present (R¹ not present if Y¹ is H, R² not present if Y² is H),C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, cyclopropyl; z is 0, 1, 2 or 3; and R³is/are independently selected from F, CH₃ or CF₃; with the proviso thatat least one of Y¹ or Y² are selected as O or S.

In yet a preferred embodiment of the invention, X is selected from I,CN, S—(C₁-C₂ alkyl), S—(C₁-C₂ fluoroalkyl), C₂-C₃ alkyl, C₁-C₃fluoroalkyl; Y¹ is selected from H, O, S, CH₃ or halogen; Y² is selectedfrom H, O, S, CH₃ or halogen. R¹ and R² are independently selected fromthe group consisting of not present (R¹ not present if Y¹ is H, CH₃ orhalogen, R² not present if Y² is H, CH₃ or halogen), C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₃-C₅ cycloalkyl; z is 0, 1, 2 or 3; and R³ is/areindependently selected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl; withthe proviso that at least one of Y¹ or Y² are selected as O or S.

In another preferred embodiment of the invention, X is selected from I,CN, S—(C₁-C₂ alkyl), S—(C₁-C₂ fluoroalkyl), C₂-C₃ alkyl, C₁-C₃fluoroalkyl; Y¹ is selected from H, O or S; Y² is selected from H, O, orS. R¹ and R² are independently selected from the group consisting of notpresent (R¹ not present if Y is H, R² not present if Y² is H), C₁-C₃alkyl, C₁-C₃ fluoroalkyl, C₃-C₅ cycloalkyl; z is 0, 1, 2 or 3; and R³is/are independently selected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl;with the proviso that at least one of Y or Y² are selected as O or S.

In yet a preferred embodiment of the invention, X is selected from I,CN, S—(C₁-C₂ alkyl), S—(C₁-C₂ fluoroalkyl), C₂-C₃ alkyl, C₁-C₃fluoroalkyl; Y¹ is selected from O, S, CH₃ or halogen; Y² is selectedfrom H, O, S, CH₃ or halogen. R¹ and R² are independently selected fromthe group consisting of not present (R¹ not present if Y¹ is CH₃ orhalogen, R² not present if Y² is H, CH₃ or halogen), C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₃-C₅ cycloalkyl; z is 0 or 1; and R³ is selected from F,C₁-C₂ alkyl or C₁-C₂ fluoroalkyl; with the proviso that at least one ofY¹ or Y² are selected as O or S.

In yet a preferred embodiment of the invention, X is selected from I,CN, S—(C₁-C₂ alkyl), S—(C₁-C₂ fluoroalkyl), C₂-C₃ alkyl, C₁-C₃fluoroalkyl; Y¹ is selected from O, S, CH₃ or halogen; Y² is selectedfrom H, O, S, CH₃ or halogen. R¹ and R² are independently selected fromthe group consisting of not present (R¹ not present if Y¹ is CH₃ orhalogen, R² not present if Y² is H, CH₃ or halogen), C₁-C₃ alkyl, C₁-C₃fluoroalkyl, cyclopropyl; z is 0 or 1; and R³ is selected from F, C₁-C₂alkyl or C₁-C₂ fluoroalkyl; with the proviso that at least one of Y¹ orY² are selected as O or S.

In yet a preferred embodiment of the invention, X is selected from I,CN, S—(C₁-C₂ alkyl), S—(C₁-C₂ fluoroalkyl), C₂-C₃ alkyl, C₁-C₃fluoroalkyl; Y¹ is selected from O, S, CH₃ or halogen; Y² could beselected from H, O, S, CH₃ or halogen. R¹ and R² are independentlyselected from the group consisting of not present (R¹ not present if Yis CH₃ or halogen, R² not present if Y² is H, CH₃ or halogen), C₁-C₃alkyl, C₁-C₃ fluoroalkyl, C₃-C₅ cycloalkyl; z is 0 or 1; and R³ isselected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl and wherein the R³group is present in any of the positions indicated as (2), (3), (4), (5)or (6) in formula (I) above, preferably in any of the positionsindicated as (2), (3) or (6) in formula (I) above, most preferably inany of the positions indicated (2) or (3) in formula (I) above; with theproviso that at least one of Y¹ or Y² are selected as O or S.

In yet a preferred embodiment of the invention, X is selected from I,CN, S—CH₃, S—CF₃, C₂-C₃ alkyl, C₁-C₃ fluoroalkyl; Y is selected from Oor S; Y² is selected from H, O, S, CH₃ or halogen. R¹ are selected fromthe group consisting of C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₃-C₅cycloalkyl; z is 0, 1, 2 or 3; and R³ is/are independently selected fromF, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl; R² are selected from the groupconsisting of not present (R² not present if Y² is H, CH₃ or halogen),C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₃-C₅ cycloalkyl; z is 0, 1, 2 or 3; andR³ is/are independently selected from F, C₁-C₂ alkyl or C₁-C₂fluoroalkyl; with the proviso that at least one of Y¹ or Y² are selectedas O or S.

In yet a preferred embodiment of the invention, X is selected from I,CN, S—CH₃, S—CF₃, C₂-C₃ alkyl, C₁-C₃ fluoroalkyl; Y¹ is selected from Oor S; Y² is selected from H, O, S, CH₃ or halogen; R¹ is selected fromC₁-C₃ alkyl, C₁-C₃ fluoroalkyl or C₃-C₅ cycloalkyl; z is 0 or 1; R³ isselected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl; R² is selected fromthe group consisting of not present (R² not present if Y² is H, CH₃ orhalogen), C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₃-C₅ cycloalkyl; z is 0 or 1;R³ is selected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl.

In yet a preferred embodiment of the invention, X is selected from I,CN, S—CH₃, S—CF₃, C₂-C₃ alkyl, C₁-C₃ fluoroalkyl; Y¹ is selected from Oor S; Y² is selected from H, O or S; R¹ is selected from the groupconsisting of C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₃-C₅ cycloalkyl; z is 0or 1; R³ is selected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl; R² isselected from the group consisting of not present (R² not present if Y²is H), C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₃-C₅ cycloalkyl; z is 0 or 1; R³is selected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl.

In yet a preferred embodiment of the invention, X is selected from I,CN, S—CH₃, S—CF₃, C₂-C₃ alkyl, C₁-C₃ fluoroalkyl; Y¹ is selected from Oor S; Y² is selected from H, O, S, CH₃ or halogen. R¹ is selected fromthe group consisting of C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₃-C₅cycloalkyl; R² is selected from the group consisting of not present (R²not present if Y² is H, CH₃ or halogen), C₁-C₃ alkyl, C₁-C₃ fluoroalkyl,C₃-C₅ cycloalkyl; z is 0 or 1; R³ is selected from F, C₁-C₂ alkyl orC₁-C₂ fluoroalkyl and wherein the R³ group is present in any of thepositions indicated as (2), (3), (4), (5) or (6) in formula (I) above,preferably in position in any of the positions indicated as (2), (3) or(6) in formula (I) above, most preferably in any of the positionsindicated as (2) or (3) in formula (I) above.

In yet a preferred embodiment of the invention, X is selected from I,CN, S—CH₃, S—CF₃, C₂-C₃ alkyl, C₁-C₃ fluoroalkyl; Y¹ is selected from Oor S; Y² is selected from H, O, or S; R¹ is selected from the groupconsisting of, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₃-C₅ cycloalkyl; R² isselected from the group consisting of not present (R² not present if Y²is H), C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₃-C₅ cycloalkyl; z is 0 or 1; R³is selected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl and wherein the R³group is present in any of the positions indicated as (2), (3), (4), (5)or (6) in formula (I) above, preferably in any of the positionsindicated as (2), (3) or (6) in formula (I) above, most preferably inany of the positions indicated as (2) or (3) in formula (I) above.

In a more preferred embodiment of the invention, X is selected from I,CN, S—CH₃, S—CF₃, C₂-C₃ alkyl, C₁-C₃ fluoroalkyl; Y¹ and Y² areindependently selected from O or S; R¹ and R² are independently selectedfrom the group consisting of C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₃-C₅cycloalkyl; z is 0, 1, 2 or 3; and R³ is/are independently selected fromF, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl.

In yet a more preferred embodiment of the invention, X is selected fromI, CN, S—CH₃, S—CF₃, C₂-C₃ alkyl, C₁-C₃ fluoroalkyl; Y¹ and Y² areindependently selected from O or S; R¹ and R² are independently selectedfrom C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or C₃-C₅ cycloalkyl; z is 0 or 1;and R³ is selected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl.

In yet a more preferred embodiment of the invention, X is selected fromI, CN, S—CH₃, S—CF₃, C₂-C₃ alkyl, C₁-C₃ fluoroalkyl; Y¹ and Y² areindependently selected from O or S; R¹ and R² are independently selectedfrom C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or C₃-C₅ cycloalkyl; z is 0 or 1;and R³ is selected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl and whereinthe R³ group is present in any of the positions indicated as (2), (3),(4), (5) or (6) in formula (I) above, preferably in any of the positionsindicated as (2), (3) or (6) in formula (I) above, most preferably inany of the positions indicated as (2) or (3) in formula (I) above.

In an even more preferred embodiment of the invention, X is selectedfrom I, CF₃, CN, S—CH₃, S—CF₃; Y and Y² are O; R¹ and R² areindependently selected from the group consisting of C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₃-C₅ cycloalkyl; z is 0, 1 or 2; and R³ is/areindependently selected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl.

In yet an even more preferred embodiment of the invention, X is selectedfrom I, CF₃, CN, S—CH₃, S—CF₃; Y¹ and Y² are independently selected fromO or S; R¹ and R² are independently selected from the group consistingof C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₃-C₅ cycloalkyl; z is 0, 1 or 2; andR³ is/are independently selected from F, C₁-C₂ alkyl or C₁-C₂fluoroalkyl.

In yet an even more preferred embodiment of the invention, X is selectedfrom I, CF₃, CN, S—CH₃, S—CF₃; Y¹ and Y² are independently selected fromO or S; R¹ and R² are independently selected from the group consistingof C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₃-C₅ cycloalkyl; z is 0 or 1; and R³is/are independently selected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl.

In yet an even more preferred embodiment of the invention, X is selectedfrom I, CF₃, CN, S—CH₃, S—CF₃; Y¹ and Y² are independently selected fromO or S; R¹ and R² are independently selected from the group consistingof C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₃-C₅ cycloalkyl; z is 0 or 1; and R³is/are independently selected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyland wherein the R³ group is present in any of the positions indicated as(2), (3), (4), (5) or (6) in formula (I) above, preferably in any of thepositions indicated as (2), (3) or (6) in formula (I) above, mostpreferably in any of the positions indicated as (2) or (3) in formula(I) above.

In yet an even more preferred embodiment of the invention, X is selectedfrom I, CF₃, CN, S—CH₃, S—CF₃; Y¹ and Y² are O; R¹ and R² areindependently selected from the group consisting of C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₃-C₅ cycloalkyl; z is 0 or 1; and R³ is selected from F,C₁-C₂ alkyl or C₁-C₂ fluoroalkyl.

In yet an even more preferred embodiment of the invention, X is selectedfrom I, CF₃, CN, S—CH₃, S—CF₃; Y¹ and Y² are O; R¹ and R² areindependently selected from the group consisting of C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₃-C₅ cycloalkyl; z is 0 or 1; and R³ is selected from F,C₁-C₂ alkyl or C₁-C₂ fluoroalkyl and wherein the R³ group is present inany of the positions indicated as (2), (3), (4), (5) or (6) in formula(I) above, preferably in any of the positions indicated as (2), (3) or(6) in formula (I) above, most preferably in any of the positionsindicated as (2) or (3) in formula (I) above.

In a yet a more preferred embodiment of the invention, X is selectedfrom I, CF₃, CN, S—CH₃, S—CF₃; Y¹ and Y² are independently selected fromO or S; R¹ and R² are independently selected from the group consistingof C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, cyclopropyl; z is 0, 1 or 2; and R³is/are independently selected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl.

In a yet a more preferred embodiment of the invention, X is selectedfrom I, CF₃, CN, S—CH₃, S—CF₃; Y and Y² are O; R¹ and R² areindependently selected from the group consisting of C₁-C₃ alkyl, C₁-C₃fluoroalkyl, cyclopropyl; z is 0 or 1; and R³ is independently selectedfrom F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl.

In a yet a more preferred embodiment of the invention, X is selectedfrom I, CF₃, CN, S—CH₃, S—CF₃; Y and Y² are O; R¹ and R² areindependently selected from the group consisting of C₁-C₃ alkyl, C₁-C₃fluoroalkyl, cyclopropyl; z is 0 or 1; and R³ is independently selectedfrom F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl and wherein the R³ group ispresent in any of the positions indicated as (2), (3), (4), (5) or (6)in formula (I) above, preferably in any of the positions indicated as(2), (3) or (6) in formula (I) above, most preferably in any of thepositions indicated as (2) or (3) in formula (I) above.

In a yet a more preferred embodiment of the invention, X is selectedfrom I, CF₃, CN, S—CH₃, S—CF₃; Y and Y² are independently selected fromO or S; R¹ and R² are independently selected from the group consistingof C₁-C₂ alkyl; z is 0 or 1; and R³ is selected from F, CH₃, CF₃.

In a yet a more preferred embodiment of the invention, X is selectedfrom I, CF₃, CN, S—CH₃, S—CF₃; Y¹ and Y² are independently selected fromO or S; R¹ and R² are independently selected from the group consistingof C₁-C₂ alkyl; z is 0 or 1; and R³ is selected from F, CH₃, CF₃ andwherein the R³ group is present in any of the positions indicated as(2), (3), (4), (5) or (6) in formula (I) above, preferably in any of thepositions indicated as (2), (3) or (6) in formula (I) above, mostpreferably in any of the positions indicated as (2) or (3) in formula(I) above.

In a highly preferred embodiment of the invention, X is selected from I,CF₃, CN, S—(C₁-C₂ alkyl), S—CF₃; Y¹ and Y² are independently selected asO or S; R¹ and R² are independently selected from the group consistingof C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, cyclopropyl; z is 0, 1, 2 or 3; andR³ is/are independently selected from F, methyl (CH₃) or trifluoromethyl(CF₃).

In yet a highly preferred embodiment of the invention, X is selectedfrom I, CF₃, CN, S—(C₁-C₂ alkyl), S—CF₃; Y¹ and Y² are independentlyselected as O or S; R¹ and R² are independently selected from the groupconsisting of C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, cyclopropyl; z is 0 or 1;and R³ is/are independently selected from F, methyl (CH₃) ortrifluoromethyl (CF₃).

In yet a highly preferred embodiment of the invention, X is selectedfrom I, CF₃, CN, S—CH₃, S—CF₃; Y¹ and Y² are O; R¹ and R² areindependently selected from the group consisting of C₁-C₂ alkyl; z is 0or 1; and R³ is selected from F, methyl (CH₃) or trifluoromethyl (CF₃).

In yet a highly preferred embodiment of the invention, X is selectedfrom I, CF₃, CN, S—CH₃, S—CF₃; Y and Y² are independently selected fromO or S; R¹ and R² are independently selected from the group consistingof C₁-C₂ alkyl; z is 0 or 1; and R³ is selected from F, methyl (CH₃) ortrifluoromethyl (CF₃) and wherein the R³ group is present in any of thepositions indicated as (2), (3), (4), (5) or (6) in formula (I) above,preferably in any of the positions indicated as (2), (3) or (6) informula (I) above, most preferably in any of the positions indicated as(2) or (3) in formula (I) above.

In a more highly preferred embodiment of the invention, X is selectedfrom I, CF₃, CN, S—CH₃, S—CF₃; Y and Y² are independently selected fromO or S; R¹ and R² are independently selected from the group consistingof C₁-C₃ alkyl; z is 0 or 1; and R³ is selected from methyl (CH₃) ortrifluoromethyl (CF₃).

In yet a more highly preferred embodiment of the invention, X isselected from I, CF₃, CN, S—CH₃, S—CF₃; Y¹ and Y² are O; R¹ and R² areindependently selected from the group consisting of C₁-C₃ alkyl, C₁-C₃fluoroalkyl; z is 0 or 1; and R³ is selected from F, methyl (CH₃) ortrifluoromethyl (CF₃) and wherein the R³ group is present in any of thepositions indicated as (2), (3), (4), (5) or (6) in formula (I) above,preferably in any of the positions indicated as (2), (3) or (6) informula (I) above, most preferably in any of the positions indicated as(2) or (3) in formula (I) above.

In yet a more highly preferred embodiment of the invention, X isselected from I, CF₃, CN, S—CH₃, S—CF₃; Y¹ and Y² are O; R¹ and R² areindependently selected from the group consisting of C₁-C₂ alkyl, C₁-C₂fluoroalkyl; z is 0 or 1; and R³ is selected from F, methyl (CH₃) ortrifluoromethyl (CF₃) and wherein the R³ group is present in any of thepositions indicated as (2), (3), (4), (5) or (6) in formula (I) above,preferably in any of the positions indicated as (2), (3) or (6) informula (I) above, most preferably in any of the positions indicated as(2) or (3) in formula (I) above.

In yet a more highly preferred embodiment of the invention, X isselected from I, CF₃, CN, S—CH₃, S—CF₃; Y¹ and Y² are O; R¹ and R² areindependently selected from the group consisting of C₁-C₂ alkyl; z is 0or 1; and R³ is selected from F, methyl (CH₃) or trifluoromethyl (CF₃)and wherein the R³ group is present in any of the positions indicated as(2), (3), (4), (5) or (6) in formula (I) above, preferably in any of thepositions indicated as (2), (3) or (6) in formula (I) above, mostpreferably in any of the positions indicated as (2) or (3) in formula(I) above.

In yet a more highly preferred embodiment of the invention, X isselected from I, CF₃, S—CH₃, S—CF₃, Y¹ is O and Y² is selected from O orS; R¹ and R² are independently selected from the group consisting ofC₁-C₂ alkyl, z is 0 or 1, and R³ is/are selected from F, methyl (CH₃) ortrifluoromethyl (CF₃).

In yet a more highly preferred embodiment of the invention, X isselected from I or CF₃; Y¹ and Y² are O; R¹ and R² are methyl (CH₃); zis 0 or 1, and R³ is independently selected from F, methyl (CH₃) ortrifluoromethyl (CF₃), most preferably methyl (CH₃) and wherein the R³group is present in any of the positions indicated as (2), (3), (4), (5)or (6) in formula (I) above, preferably in any of the positionsindicated as (2), (3) or (6) in formula (I) above, most preferably inany of the positions indicated as (2) or (3) in formula (I) above.

In the most preferred embodiment of the invention, X is CF₃; Y¹ and Y²are O; R¹ and R² are methyl (CH₃) and z is 0.

In any of the above-mentioned embodiments R⁴ is most preferably selectedas H. In any of the above-mentioned embodiments Y¹ and Y² are mostpreferably selected as O. In any of the above-mentioned embodiments z ismost preferably 0 or 1. In any of the above-mentioned embodiments R³ ismost preferably methyl (CH₃).

Aspect 2—Selective 5-HT_(2A) Agonists

In the second aspect the invention relates to selective 5-HT_(2A)agonists of the general formula (II)

or a pharmaceutically acceptable salt thereof wherein:

X is selected from the group consisting of I, CN, S—(C₁-C₅ alkyl),S—(C₁-C₅ fluoroalkyl), S—(C₂-C₅ alkenyl), S—(C₂-C₅ fluoroalkenyl),S—(C₂-C₅ alkynyl), S—(C₂-C₅ fluoroalkynyl), C₂-C₅ alkyl, C₁-C₅fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅ fluoroalkenyl, C₂-C₅ alkynyl and C₂-C₅fluoroalkynyl;

Y¹ and Y² are independently selected from the group consisting of H, O,S, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and halogen;

R¹ is not present when Y¹ is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

R² is not present when Y² is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

when present, R¹ and R² are independently selected from the groupconsisting of C₁-C₅ alkyl, C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅fluoroalkenyl, C₂-C₅ alkynyl, C₂-C₅ fluoroalkynyl, C₃-C₅ cycloalkyl andC₃-C₅ fluorocycloalkyl;

z denotes the number of R³ groups and is an integer with a value of 0,1, 2, 3 or 4;

R³ is/are independently selected from the group consisting of F, C₁-C₃alkyl, C₁-C₃ fluoroalkyl, C₂-C₃ alkenyl or C₂-C₃ alkynyl;

with the proviso that at least one of Y¹ or Y² are selected as O or S.

Substituent X

The inventors found that the substituent X in Formula (II) was importantfor the potency of the 5-HT_(2A) agonists and that X tolerated a varietyof lipophilic substituents. The skilled person is aware of a range ofsubstituents that are suitable to fulfill the role as a lipophilicsubstituent. Thus, in an embodiment of the invention, X is selected fromI, CN, S—(C₁-C₅ alkyl), S—(C₁-C₅ fluoroalkyl), C₂-C₅ alkyl, C₁-C₅fluoroalkyl. In a preferred embodiment, X is selected from I, CN,S—(C₁-C₄ alkyl), S—(C₁-C₄ fluoroalkyl), C₂-C₄ alkyl, C₁-C₄ fluoroalkyl.In yet a preferred embodiment, X is selected from I, CN, S—(C₁-C₃alkyl), S—(C₁-C₃ fluoroalkyl), C₂-C₃ alkyl, C₁-C₃ fluoroalkyl. In yet apreferred embodiment, X is selected from I, CN, S—(C₁-C₃ alkyl),S—(C₁-C₃ fluoroalkyl), C₂-C₅ alkyl, C₁-C₅ fluoroalkyl. In a morepreferred embodiment, X is selected from I, CN, S—CH₃, S—CF₃, C₂-C₃alkyl, C₁-C₃ fluoroalkyl. In an even more preferred embodiment of theinvention, X is selected from I, CF₃, CN, S—CH₃, S—CF₃. In a yet an evenmore preferred embodiment, X is selected from I, CF₃, CN, S—CH₃. In ahighly preferred embodiment, X is selected from I, CF₃, S—CH₃. In aneven more highly preferred embodiment of the invention, X is selectedfrom I or CF₃. In the most preferred embodiment of the invention, X isselected from CF₃.

Substituents Y¹ and Y²

The inventors further found that Y¹ and Y² could independently beselected from H, O, S, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, or halogen withthe proviso that at least one of Y¹ or Y² is selected as O or S. Itfollows that when Y¹ is H, halogen, C₁-C₃ fluoroalkyl or C₁-C₃ alkyl, R¹is not present (deleted). Likewise, when Y² is H, halogen, C₁-C₃fluoroalkyl, or C₁-C₃ alkyl, R² is not present (deleted). In anembodiment of the invention Y¹ is selected from O, S, CH₃ or halogen andY² is selected from O, S, CH₃ or halogen. In a preferred embodiment ofthe invention Y is selected from O, S, H or halogen and Y² is selectedfrom O, S, H or halogen. In yet a preferred embodiment Y¹ is selectedfrom O, S, or CH₃ and Y² is selected from O, S, or CH₃. In a morepreferred embodiment of the invention Y is selected from O, S or H andY² is selected from O, S or H. In yet a more preferred embodiment Y¹ isselected from O or S and Y² is selected from O or S. In yet a preferredembodiment, Y¹ is selected from O or S, and Y² is selected from H,halogen, O or S. In particular, the presence of a heteroatom in Y¹ andY² provided potent 5-HT_(2A) agonists. Thus, in an embodiment of theinvention, Y¹ is O, and Y² is S. In another embodiment of the invention,Y is S, and Y² is O. In yet another embodiment, Y¹ and Y² are S. In themost preferred embodiment of the invention, Y¹ and Y² are O.

Substituent R¹ and R²

The inventors surprisingly found that the pharmacophore occupied by R¹and R² in formula (II) allowed small lipophilic substituents whilemaintaining 5-HT_(2A) activity and potency of the compounds. Thus, in anembodiment of the invention, R¹ and R² are independently selected fromthe group consisting of not present (R¹ not present if Y is H, C₁-C₃alkyl, C₁-C₃ fluoroalkyl or halogen, R² not present if Y² is H, C₁-C₃alkyl, C₁-C₃ fluoroalkyl or halogen), C₁-C₅ alkyl, C₁-C₅ fluoroalkyl,C₃-C₅ cycloalkyl and C₃-C₅ fluorocycloalkyl. In a preferred embodimentof the invention, R¹ and R² are independently selected from the groupconsisting of C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₃-C₅ cycloalkyl and C₃-C₅fluorocycloalkyl. In yet a more preferred embodiment, R¹ and R² areindependently selected from the group consisting of C₁-C₃ alkyl, C₁-C₃fluoroalkyl and C₃-C₅ cycloalkyl. In yet an even more preferredembodiment of the invention, R¹ and R² are independently selected fromthe group consisting of C₁-C₃ alkyl, C₁-C₃ fluoroalkyl and cyclopropyl.In an even more preferred embodiment, R¹ and R² are independentlyselected from the group consisting of C₁-C₃ alkyl and C₁-C₃ fluoroalkyl.In a highly preferred embodiment, R¹ and R² are independently selectedfrom the group consisting of C₁-C₂ alkyl and C₁-C₂ fluoroalkyl. Inanother highly preferred embodiment, R¹ and R² are independentlyselected from C₁-C₂ alkyl. In an even more preferred embodiment, R¹ andR² are independently selected from the group consisting of methyl (CH₃)and trifluoromethyl (CF₃). In the most preferred embodiment of theinvention, R¹ and R² are both methyl (CH₃).

Number (z) of R³ Substituent(s) and Preferred Positions

The inventors further found that the carbon atoms in the piperidine ringsystem could be substituted with small lipophilic substituents (R³).Thus, according to the present invention, the one or more R³substituent(s) (if present) is/are present at any of the positions (2),(3), (4), (5) and/or (6) as shown in formula (II) below. Morepreferably, one or more R³ substituent(s) (if present) is/are present atany of the positions (2), (3) and/or (6) as shown in in formula (II)below, most preferably at position (2) or (3) as shown in in formula(II) below. It follows that two R³ substituents may be present on thesame position (carbon atom). The inventors found that the secondaryamine (free NH) in the piperidine ring system was highly important formaintaining high agonist activity at the 5-HT_(2A) receptor, whereasnitrogen substituents (tertiary amines) led to a significant loss ofpotency at 5-HT_(2A) (factor ˜80 for compound 59 (N-Et) and a factor ˜20for compound 61 (N-Me) compared to compound 8). Furthermore,N-methylation of the piperidine resulted in a loss of selectivity for5-HT_(2A) over 5-HT_(2C) as shown for compound 61 in comparison withcompound 8. Thus, in the second aspect the piperidine comprises asecondary amine (free NH) (i.e. the piperidine is not N-methylated).

Thus, in an embodiment of the invention, z is 0-4 such that thepiperidine is unsubstituted or substituted with 1-4 R³ groups. In apreferred embodiment of the invention, z is 0-3 such that the piperidineis unsubstituted or substituted with 1-3 R³ groups. In a more preferredembodiment of the invention, z is 0-2 such that the piperidine isunsubstituted or substituted with 1-2 R³ groups. In an even morepreferred embodiment of the invention, z is 0-1 such that the piperidineis unsubstituted or substituted with one R³ group. In the most preferredembodiment of the invention z is O, such that no R³ substituents arepresent.

In a preferred embodiment of the invention, z is 0 or 1, such that thepiperidine is unsubstituted or substituted with one R³ group, andwherein the one R³ group is present in the positions (2), (3), (4), (5)or (6) as shown in formula (II) above, preferably in the any of thepositions indicated as (2), (3) or (6) as shown in formula (II) above,most preferably in any of the position indicated as (2) or (3) informula (II) above.

Type of R³ Substituent(s)

In an embodiment of the invention, the R³ group(s) is/are independentlyselected from the group consisting of F, C₁-C₃ alkyl or C₁-C₃fluoroalkyl. In a preferred embodiment of the invention, the R³ group(s)is/are independently selected from the group consisting of F, C₁-C₂alkyl or C₁-C₂ fluoroalkyl. In the highly preferred embodiment of theinvention, the R³ group(s) is/are independently selected from the groupconsisting of F, methyl (CH₃) or trifluoromethyl (CF₃). In the mostpreferred embodiment of the invention, the R³ group(s) is/areindependently selected from the group consisting of F, methyl (CH₃),most preferably methyl (CH₃).

Stereochemistry

In the second aspect, the compound is a stereoisomer with the absolutestereochemistry at the chiral center as drawn in Formula (II) (i.e.(S)-stereoisomer). It is evident to the skilled person that in case ofR³ substituents on the piperidine, one or more additional chiral centersmay be present in the molecule. These other chiral centers may be eitherin the (R) and (S) configuration in accordance with Cahn-Ingold-Prelogpriority rules. The number of stereoisomers possible depends on thenumber of chiral centers present and can be calculated as 2^(n), where nis the number of additional chiral centers. In the present context, theinvention is intended to cover all the single stereoisomers possible aswell as any mixture thereof. The stereoisomers according to the presentinvention may be separated using conventional methods in the art. Thus,diastereomers may be separated by selective crystallization, liquidcolumn chromatography, such as conventional silica gel chromatography orHigh Performance Liquid Chromatography (HPLC) (reverse andnormal-phase). Furthermore, enantiomers may be separated using chiralresolution, such as chiral HPLC, chiral SFC or chiral derivatizingagents to form diastereomers that may be separated with any of theabove-mentioned conventional methods.

Preferred Embodiments

In a preferred embodiment of the invention, X is selected from I, CN,S—(C₁-C₅ alkyl), S—(C₁-C₅ fluoroalkyl), S—(C₂-C₅ alkenyl), S—(C₂-C₅fluoroalkenyl), S—(C₂-C₅ alkynyl), S—(C₂-C₅ fluoroalkynyl), C₂-C₅ alkyl,C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅ fluoroalkenyl, C₂-C₅ alkynyl orC₂-C₅ fluoroalkynyl; Y¹ and Y² are independently selected from H, O, S,CH₃ or halogen; R¹ and R² are independently selected from the notpresent (R¹ not present if Y is H, CH₃ or halogen, R² not present if Y²is H, CH₃ or halogen), C₁-C₅ alkyl, C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl,C₂-C₅ fluoroalkenyl, C₂-C₅ alkynyl, C₂-C₅ fluoroalkynyl, C₃-C₅cycloalkyl or C₃-C₅ fluorocycloalkyl; z denotes the number of R³ groupsand is an integer with a value of 0, 1, 2, 3 or 4; R³ is/areindependently selected from F, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₂-C₃alkenyl or C₂-C₃ alkynyl; with the proviso that at least one of Y¹ or Y²is selected as O or S.

In yet a preferred embodiment of the invention, X is selected from I,CN, S—CH₃, S F₃, C₂-C₃ alkyl, C₁-C₃ fluoroalkyl; Y¹ and Y² areindependently selected from O, S, CH₃ or halogen; R¹ and R² areindependently selected from not present (R¹ not present if Y¹ is CH₃ orhalogen, R² not present if Y² is CH₃ or halogen), C₁-C₃ alkyl, C₁-C₃fluoroalkyl or C₃-C₅ cycloalkyl; z is 0, 1, 2 or 3; and R³ is/areindependently selected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl; withthe proviso that at least one of Y or Y² is selected as O or S.

In yet a preferred embodiment of the invention, X is selected from I,CN, S—CH₃, S—CF₃, C₂-C₃ alkyl or C₁-C₃ fluoroalkyl; Y¹ and Y² areindependently selected from O, CH₃, or S; R¹ and R² are independentlyselected from not present (R¹ not present if Y¹ is CH₃R² not present ifY² is CH₃), C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or C₃-C₅ cycloalkyl; z is 0,1, 2 or 3; and R³ is/are independently selected from F, C₁-C₂ alkyl orC₁-C₂ fluoroalkyl.

In a more preferred embodiment of the invention, X is selected from I,CN, S—CH₃, S—CF₃, C₂-C₃ alkyl or C₁-C₃ fluoroalkyl; Y¹ and Y² areindependently selected from O or S; R¹ and R² are independently selectedfrom C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or C₃-C₅ cycloalkyl; z is 0, 1, 2 or3; and R³ is/are independently selected from F, C₁-C₂ alkyl or C₁-C₂fluoroalkyl.

In an even more preferred embodiment of the invention, X is selectedfrom I, CF₃, CN, S—CH₃, S—CF₃; Y¹ and Y² are O; R¹ and R² areindependently selected from the group consisting of C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₃-C₅ cycloalkyl; z is 0, 1 or 2; and R³ is/areindependently selected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl.

In a yet more preferred embodiment of the invention, X is selected fromI, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are O; R¹ and R² are independentlyselected from C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or cyclopropyl; z is 0, 1or 2; and R³ is/are independently selected from F, C₁-C₂ alkyl or C₁-C₂fluoroalkyl.

In a highly preferred embodiment of the invention, X is selected from I,CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are O; R¹ and R² are independentlyselected from C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or cyclopropyl; z is 0, 1,2 or 3; and R³ is/are independently selected from F, methyl (CH₃) ortrifluoromethyl (CF₃).

In more highly preferred embodiment of the invention, X is selected fromI, CF₃, CN, S—CH₃, S—CF₃; Y and Y² are O; R¹ and R² are independentlyselected from the group consisting of C₁-C₃ alkyl, C₁-C₃ fluoroalkyl; zis 0, 1 or 2; and R³ is/are independently selected from F, methyl (CH₃)or trifluoromethyl (CF₃).

In yet a more highly preferred embodiment of the invention, X isselected from I, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are O; R¹ and R² areindependently selected from C₁-C₂ alkyl or C₁-C₂ fluoroalkyl; z is 0, 1or 2; and R³ is/are independently selected from F, methyl (CH₃) ortrifluoromethyl (CF₃).

In yet a more highly preferred embodiment of the invention, X isselected from I, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are O; R¹ and R² areindependently selected from C₁-C₂ alkyl or C₁-C₂ fluoroalkyl; z is 0 or1; and R³ is/are selected from F, methyl (CH₃) or trifluoromethyl (CF₃).

In yet a more highly preferred embodiment of the invention, X isselected from I, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are O; R¹ and R² areindependently selected from C₁-C₂ alkyl; z is 0 or 1; and R³ is/areselected from F, methyl (CH₃) or trifluoromethyl (CF₃).

In yet a more highly preferred embodiment of the invention, X isselected from I or CF₃; Y¹ and Y² are O; R¹ and R² are methyl (CH₃); zis 0, 1 or 2, and R³ is/are independently selected from F, methyl (CH₃)or trifluoromethyl (CF₃).

In the most preferred embodiment of the invention, X is CF₃; Y¹ and Y²are O; R¹ and R² are methyl (CH₃) and z is 0.

Furthermore, any preferred embodiments mentioned under aspect 1 applyequally well to aspect 2 for the compounds of formula (II).

Aspect 3—Mixed 5-HT_(2A)/5-HT_(2C) Agonists

In the third aspect, the invention relates to 5-HT_(2A)/5-HT_(2C)agonists of the general formula (III)

or a pharmaceutically acceptable salt thereof wherein:

X is selected from the group consisting of I, CN, S—(C₁-C₅ alkyl),S—(C₁-C₅ fluoroalkyl), S—(C₂-C₅ alkenyl), S—(C₂-C₅ fluoroalkenyl),S—(C₂-C₅ alkynyl), S—(C₂-C₅ fluoroalkynyl), C₂-C₅ alkyl, C₁-C₅fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅ fluoroalkenyl, C₂-C₅ alkynyl, andC₂-C₅ fluoroalkynyl;

Y¹ and Y² are independently selected from the group consisting of H, O,S, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and halogen;

R¹ is not present when Y is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

R² is not present when Y² is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

when present, R¹ and R² are independently selected from the groupconsisting of C₁-C₅ alkyl, C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅fluoroalkenyl, C₂-C₅ alkynyl, C₂-C₅ fluoroalkynyl, C₃-C₅ cycloalkyl orC₃-C₅ fluorocycloalkyl;

* denotes the (R) or (S) stereoisomer or any mixture thereof if a chiralcenter is present;

n is an integer with a value of 1, 2, 3 or 4 to form an azetidine,pyrrolidine, piperidine or azepane ring system;

z denotes the number of R³ groups and is an integer with a value of 0,1, 2, 3 or 4;

R³ is/are independently selected from the group consisting of F, C₁-C₃alkyl, C₁-C₃ fluoroalkyl, C₂-C₃ alkenyl and C₂-C₃ alkynyl;

R⁴ is selected from H or CH₃;

with the proviso that when n=3, * denotes the (R) stereoisomer andfurther with the proviso that at least one of Y¹ or Y² are selected as Oor S.

In the third aspect, X, Y¹, Y², R¹, R², z and R³ are selected with thesame preference as in aspect 1 or 2. Thus, the embodiments under all theheadings “Substituent X”, “Substituents Y¹ and Y²”, “Substituents R¹ andR²”, “Number (z) of R³ substituents and preferred positions” and “Typeof R³ substituent(s)” apply equally to aspect 3. Likewise, the preferredembodiments described under aspect 1 and 2 apply equally to aspect 3 forall the ring systems (i.e. the azetidine, pyrrolidine, piperidine orazepane ring system).

In the most preferred embodiments R⁴ is H.

Stereochemistry (*)

The inventors surprisingly found that both the (R) and (S)-stereoisomersof Formula (IV), (V) and (VI) shown below resulted in potent5-HT_(2A)/5-HT_(2C) agonists with minor selectivity towards the5-HT_(2A) receptor over 5-HT_(2C) receptor (approximately a factor 2-5in EC₅₀ values), when measured in the Ca²⁺/Fluo-4 functional assay asdescribed herein. It should be noted that in some cases, no chiralcenter is present (e.g. when n=1 to form an azetidine with no R³substituents). Likewise, the (R)-stereoisomers shown in Formula (VII)(i.e. (R)-piperidines) also provided 5-HT_(2A) agonists with mixed5-HT_(2A)/5-HT_(2C) agonist profiles and with minor selectivity towardsthe 5-HT_(2A) receptor over 5-HT_(2C) receptor (approximately a factor2-10 in EC₅₀), when measured in the Ca²⁺/Fluo-4 functional assay.However, these agonists had a significant loss of potency (approximately13-70-fold on 5-HT_(2A) and a 20-70-fold on 5-HT_(2C) when compared withthe (R)-pyrrolidines). Thus, in a preferred embodiment of aspects 3 and6, n is an integer with a value of 1, 2 or 4, more preferably n is aninteger with a value of 1 or 2, most preferably n is an integer with avalue of 1.

In aspects 3 and 6 of the invention, (*) is intended to cover both the(R) and (S)-stereoisomers of Formula (IV), (V), (VI) shown above (i.e.the enantiomers when no other chiral centers are present) as well as anymixture thereof and the (R)-stereoisomers of Formula (VII). It isevident to the skilled person that in case of R³ substituents on thesaturated heterocycle (i.e. the azetidine, pyrrolidine, piperidine orazepane ring system) one or more additional chiral centers may bepresent in the molecule. The number of stereoisomers possible depends onthe number of chiral centers present and can be calculated as 2^(n),where n is the number of chiral centers. In the present context, theinvention is intended to cover all the single stereoisomers possible aswell as any mixture thereof. The stereoisomers according to the presentinvention may be separated using conventional methods in the art asdescribed under aspect 1.

Aspect 4—Medical Use of 5-HT_(2A) Agonists

In the fourth aspect, the invention relates to 5-HT_(2A) agonists of thegeneral formula (I) or a pharmaceutically acceptable salt thereof foruse as a medicament

wherein:

* denotes the (R) or (S) stereoisomer or any mixture thereof;

X is selected from the group consisting of F, Cl, Br, I, CN, S—(C₁-C₅alkyl), S—(C₁-C₅ fluoroalkyl), S—(C₂-C₅ alkenyl), S—(C₂-C₅fluoroalkenyl), S—(C₂-C₅ alkynyl), S—(C₂-C₅ fluoroalkynyl), C₁-C₅ alkyl,C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅ fluoroalkenyl, C₂-C₅ alkynyl,and C₂-C₅ fluoroalkynyl;

Y¹ and Y² are independently selected from the group consisting of H, O,S, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and halogen;

R¹ is not present when Y¹ is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

R² is not present when Y² is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

when present, R¹ and R² are independently selected from the groupconsisting of C₁-C₅ alkyl, C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅fluoroalkenyl, C₂-C₅ alkynyl, C₂-C₅ fluoroalkynyl, C₃-C₅ cycloalkyl andC₃-C₅ fluorocycloalkyl;

z denotes the number of R³ groups and is an integer with a value of 0,1, 2, 3 or 4;

R³ is/are independently selected from the group consisting of F, C₁-C₃alkyl, C₁-C₃ fluoroalkyl, C₂-C₃ alkenyl and C₂-C₃ alkynyl;

R⁴ is selected from H or CH₃;

with the proviso that at least one of Y¹ or Y² are selected as O or S.

In the fourth aspect, Y¹, Y², R¹, R², z, and R³ are selected with thesame preference as in aspects 1 and 2. Thus, the embodiments under theheadings “Substituents Y¹ and Y²”, “Substituents R¹ and R²”, “Number (z)of R³ substituents and preferred positions” and “Type of R³substituent(s)” in aspects 1 and 2 apply equally well to aspect 4.Furthermore, the preferred embodiments in aspects 1 and 2 also apply toaspect 4. In addition, the description under the heading“Stereochemistry” in aspect 1 applies equally to aspect 4.

Substituent X on the Aromatic Ring

For aspects 4, 5 and 6 (i.e. medical use aspects/method of treatmentaspects), X further includes CH₃, F, Cl and Br. Thus, in an embodimentof aspects 4, 5 or 6, X is selected from F, Cl, Br, I, CN, S—(C₁-C₅alkyl), S—(C₁-C₅ fluoroalkyl), C₁-C₅ alkyl or C₁-C₅ fluoroalkyl. In apreferred embodiment, X is selected from F, Cl, Br, I, CN, S—(C₁-C₃alkyl), S—(C₁-C₃ fluoroalkyl), C₁-C₅ alkyl or C₁-C₅ fluoroalkyl. In yeta preferred embodiment, X is selected from F, Cl, Br, I, CN, S—(C₁-C₄alkyl), S—(C₁-C₄ fluoroalkyl), C₁-C₄ alkyl or C₁-C₄ fluoroalkyl. In yeta preferred embodiment, X is selected from F, Cl, Br, I, CN, S—(C₁-C₃alkyl), S—(C₁-C₃ fluoroalkyl), C₁-C₃ alkyl or C₁-C₃ fluoroalkyl. In yeta preferred embodiment, X is selected from F, Cl, Br, I, CN, S—(C₁-C₂alkyl), S—(C₁-C₂ fluoroalkyl), C₁-C₂ alkyl or C₁-C₂ fluoroalkyl. In yeta preferred embodiment, X is selected from F, Cl, Br, I, CN, S—(C₁-C₂alkyl), C₁-C₂ alkyl or C₁-C₂ fluoroalkyl. In a more preferredembodiment, X is selected from Cl, Br, I, CN, S—CH₃, S—CF₃, C₁-C₃ alkylor C₁-C₃ fluoroalkyl. In an even more preferred embodiment of theinvention, X is selected from Cl, Br, I, CH₃, CF₃, CN, S—CH₃ or S—CF₃.In a yet an even more preferred embodiment, X is selected from Cl, Br,I, CF₃, CN or S—CH₃. In a highly preferred embodiment, X is selectedfrom Cl, Br, I, CF₃ or S—CH₃. In another highly preferred embodiment, Xis selected from Cl, Br, I, or CF₃. In an even more highly preferredembodiment, X is selected from Cl, I, or CF₃. In a yet even more highlypreferred embodiment, X is selected from I or CF₃. In the most preferredembodiment of the invention, X is selected from CF₃.

Preferred Embodiments

In a preferred embodiment of the invention, X is selected from F, Cl,Br, I, CN, S—(C₁-C₃ alkyl), S—(C₁-C₃ fluoroalkyl), C₁-C₃ alkyl, C₁-C₃fluoroalkyl; Y¹ is selected from H, O, S, CH₃ or halogen; Y² is selectedfrom H, O, S, CH₃ or halogen. R¹ and R² are independently selected fromnot present (R¹ not present if Y¹ is H, CH₃ or halogen, R² not presentif Y² is H, CH₃ or halogen), C₁-C₃ alkyl, C₁-C₃ fluoroalkyl orcyclopropyl; z is 0, 1, 2 or 3; and R³ is/are independently selectedfrom F, CH₃ or CF₃; with the proviso that at least one of Y¹ or Y² isselected as O or S.

In yet a preferred embodiment of the invention, X is selected from F,Cl, Br, I, CN, S—(C₁-C₃ alkyl), S—(C₁-C₃ fluoroalkyl), C₁-C₃ alkyl orC₁-C₃ fluoroalkyl; Y¹ is selected from H, O, or S; Y² is selected fromH, O, or S. R¹ and R² are independently selected from the groupconsisting of not present (R¹ not present if Y¹ is H, R² not present ifY² is H), C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, cyclopropyl; z is 0, 1, 2 or3; and R³ is/are independently selected from F, CH₃ or CF₃; with theproviso that at least one of Y¹ or Y² is selected as O or S.

In yet a preferred embodiment of the invention, X is selected from F,Cl, Br, I, CN, S—(C₁-C₂ alkyl), S—CF₃, C₁-C₃ alkyl or C₁-C₃ fluoroalkyl;Y¹ is selected from O, S, CH₃ or halogen; Y² could be selected from H,O, S, CH₃ or halogen. R¹ and R² are independently selected from notpresent (R¹ not present if Y¹ is CH₃ or halogen, R² not present if Y² isH, CH₃ or halogen), C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or C₃-C₅ cycloalkyl;z is 0, 1, 2 or 3; and R³ is/are independently selected from F, C₁-C₂alkyl or C₁-C₂ fluoroalkyl; with the proviso that at least one of Y¹ orY² is selected as O or S.

In yet a preferred embodiment of the invention, X is selected from F,Cl, Br, I, CN, S—(C₁-C₂ alkyl), S—CF₃, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl;Y¹ is selected from O, S, CH₃ or halogen; Y² is selected from H, O, S,CH₃ or halogen. R¹ and R² are independently selected from the groupconsisting of not present (R¹ not present if Y is CH₃ or halogen, R² notpresent if Y² is H, CH₃ or halogen), C₁-C₃ alkyl, C₁-C₃ fluoroalkyl,C₃-C₅ cycloalkyl; z is 0 or 1; and R³ is selected from F, C₁-C₂ alkyl orC₁-C₂ fluoroalkyl.

In yet a preferred embodiment of the invention, X is selected from F,Cl, Br, I, CN, S—(C₁-C₂ alkyl), S—CF₃, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl;Y¹ is selected from O, S, CH₃ or halogen; Y² is selected from H, O, S,CH₃ or halogen. R¹ and R² are independently selected from not present(R¹ not present if Y¹ is CH₃ or halogen, R² not present if Y² is H, CH₃or halogen), C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or C₃-C₅ cycloalkyl; z is 0or 1; and R³ is selected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl andwherein the R³ group is present in any of the positions indicated as(2), (3), (4), (5) or (6) in formula (I) above, preferably in any of thepositions indicated as (2), (3) or (6) in formula (I) above, mostpreferably in any of the positions indicated as (2) or (3) in formula(I) above.

In a preferred embodiment of the invention, X is selected from F, Cl,Br, I, CN, S—CH₃, S—CF₃, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl; Y¹ is selectedfrom O or S; Y² could be selected from H, O, S, CH₃ or halogen. R¹ isselected from C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or C₃-C₅ cycloalkyl; R² isselected from not present (R² not present if Y² is H, CH₃ or halogen),C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or C₃-C₅ cycloalkyl; z is 0, 1, 2 or 3;and R³ is/are independently selected from F, C₁-C₂ alkyl or C₁-C₂fluoroalkyl.

In yet a preferred embodiment of the invention, X is selected from F,Cl, Br, I, CN, S—CH₃, S—CF₃, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl; Y isselected from O or S; Y² is selected from H, O, S, CH₃ or halogen. R¹ isselected from C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or C₃-C₅ cycloalkyl; R² isselected from not present (R² not present if Y² is H, CH₃ or halogen),C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or C₃-C₅ cycloalkyl; z is 0 or 1; R³ isselected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl.

In yet a preferred embodiment of the invention, X is selected from F,Cl, Br, I, CN, S—CH₃, S—CF₃, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl; Y isselected from O or S; Y² is selected from H, O, S, CH₃ or halogen. R¹ isselected from C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or C₃-C₅ cycloalkyl; R² isselected from not present (R² not present if Y² is H, CH₃ or halogen),C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or C₃-C₅ cycloalkyl; z is 0 or 1; R³ isselected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl and wherein the R³group is present in any of the positions indicated as (2), (3), (4), (5)or (6) in formula (I) above, preferably in any of the positionsindicated as (2), (3) or (6) in formula (I) above, most preferably inany of the positions indicated as (2) or (3) in formula (I) above.

In a more preferred embodiment of the invention, X is selected from F,Cl, Br, I, CN, S—CH₃, S—CF₃, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl; Y¹ and Y²are independently selected from O or S; R¹ and R² are independentlyselected from C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or C₃-C₅ cycloalkyl; z is0, 1, 2 or 3; and R³ is/are independently selected from F, C₁-C₂ alkylor C₁-C₂ fluoroalkyl.

In yet a more preferred embodiment of the invention, X is selected fromF, Cl, Br, I, CN, S—CH₃, S—CF₃, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl; Y¹ andY² are independently selected from O or S; R¹ and R² are independentlyselected from the group consisting of C₁-C₃ alkyl, C₁-C₃ fluoroalkyl,C₃-C₅ cycloalkyl; z is 0 or 1; and R³ is selected from F, C₁-C₂ alkyl orC₁-C₂ fluoroalkyl.

In yet a more preferred embodiment of the invention, X is selected fromF, Cl, Br, I, CN, S—CH₃, S—CF₃, C₁-C₃ alkyl or C₁-C₃ fluoroalkyl; Y¹ andY² are independently selected from O or S; R¹ and R² are independentlyselected from C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or C₃-C₅ cycloalkyl; z is 0or 1; and R³ is selected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl andwherein the R³ group is present in any of the positions indicated as(2), (3), (4), (5) or (6) in formula (I) above, preferably in any of thepositions indicated as (2), (3) or (6) in formula (I) above, mostpreferably in any of the positions indicated as (2) or (3) in formula(I) above.

In an even more preferred embodiment of the invention, X is selectedfrom F, Cl, Br, I, CH₃, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are O; R¹ andR² are independently selected from C₁-C₃ alkyl, C₁-C₃ fluoroalkyl orC₃-C₅ cycloalkyl; z is 0, 1 or 2; and R³ is/are independently selectedfrom F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl.

In yet an even more preferred embodiment of the invention, X is selectedfrom F, Cl, Br, I, CH₃, CF₃, CN, S—CH₃, S—CF₃; Y¹ and Y² areindependently selected from O or S; R¹ and R² are independently selectedfrom the group consisting of C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₃-C₅cycloalkyl; z is 0, 1 or 2; and R³ is/are independently selected from F,C₁-C₂ alkyl or C₁-C₂ fluoroalkyl.

In yet an even more preferred embodiment of the invention, X is selectedfrom Cl, Br, I, CH₃, CF₃, CN, S—CH₃, S—CF₃; Y¹ and Y² are independentlyselected from O or S; R¹ and R² are independently selected from C₁-C₃alkyl, C₁-C₃ fluoroalkyl or C₃-C₅ cycloalkyl; z is 0 or 1; and R³ isselected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl.

In yet an even more preferred embodiment of the invention, X is selectedfrom Cl, Br, I, CH₃, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² areindependently selected from O or S; R¹ and R² are independently selectedfrom C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or C₃-C₅ cycloalkyl; z is 0 or 1;and R³ is selected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl and whereinthe R³ group is present in any of the positions indicated as (2), (3),(4), (5) or (6) in formula (I) above, preferably in any of the positionsindicated as (2), (3) or (6) in formula (I) above, most preferably inany of the positions indicated as (2) or (3) in formula (I) above.

In yet an even more preferred embodiment of the invention, X is selectedfrom Cl, Br, I, CH₃, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are O; R¹ and R²are independently selected from C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or C₃-C₅cycloalkyl; z is 0 or 1; and R³ is selected from F, C₁-C₂ alkyl or C₁-C₂fluoroalkyl.

In yet an even more preferred embodiment of the invention, X is selectedfrom Cl, Br, I, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are O; R¹ and R² areindependently selected from C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or C₃-C₅cycloalkyl; z is 0 or 1; and R³ is selected from F, C₁-C₂ alkyl or C₁-C₂fluoroalkyl and wherein the R³ group is present in any of the positionsindicated as (2), (3), (4), (5) or (6) in formula (I) above, preferablyin any of the positions indicated as (2), (3) or (6) in formula (I)above, most preferably in any of the positions indicated as (2) or (3)in formula (I) above.

In a yet a more preferred embodiment of the invention, X is selectedfrom Cl, Br, I, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are O; R¹ and R² areindependently selected from C₁-C₃ alkyl, C₁-C₃ fluoroalkyl orcyclopropyl; z is 0, 1 or 2; and R³ is/are independently selected fromF, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl.

In a yet a more preferred embodiment of the invention, X is selectedfrom Cl, Br, I, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are O; R¹ and R² areindependently selected from C₁-C₃ alkyl, C₁-C₃ fluoroalkyl orcyclopropyl; z is 0 or 1; and R³ is selected from F, C₁-C₂ alkyl orC₁-C₂ fluoroalkyl.

In a yet a more preferred embodiment of the invention, X is selectedfrom Cl, Br, I, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are O; R¹ and R² areindependently selected from C₁-C₃ alkyl, C₁-C₃ fluoroalkyl orcyclopropyl; z is 0 or 1; and R³ is selected from F, C₁-C₂ alkyl orC₁-C₂ fluoroalkyl and wherein the R³ group is present in any of thepositions indicated as (2), (3), (4), (5) or (6) in formula (I) above,preferably in any of the positions indicated as (2), (3) or (6) informula (I) above, most preferably in any of the positions indicated as(2) or (3) in formula (I) above.

In a yet a more preferred embodiment of the invention, X is selectedfrom Cl, Br, I, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are independentlyselected from O or S; R¹ and R² are independently selected from C₁-C₂alkyl; z is 0 or 1; and R³ is selected from F, CH₃ or CF₃.

In a yet a more preferred embodiment of the invention, X is selectedfrom Cl, Br, I, CF₃, CN, S—CH₃, S—CF₃; Y¹ and Y² are independentlyselected from O or S; R¹ and R² are independently selected from C₁-C₂alkyl; z is 0 or 1; and R³ is selected from F, CH₃, CF₃ and wherein theR³ group is present in any of the positions indicated as (2), (3), (4),(5) or (6) in formula (I) above, preferably in any of the positionsindicated as (2), (3) or (6) in formula (I) above, most preferably inany of the positions indicated as (2) or (3) in formula (I) above.

In a highly preferred embodiment of the invention, X is selected fromCl, Br, I, CF₃, CN, S—(C₁-C₂ alkyl) or S—CF₃; Y¹ and Y² areindependently selected from O or S; R¹ and R² are independently selectedfrom C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, cyclopropyl; z is 0, 1, 2 or 3; andR³ is/are independently selected from F, methyl (CH₃) or trifluoromethyl(CF₃).

In yet a highly preferred embodiment of the invention, X is selectedfrom Cl, Br, I, CF₃, CN, S—(C₁-C₂ alkyl) or S—CF₃; Y¹ and Y² areindependently selected from O or S; R¹ and R² are independently selectedfrom C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or cyclopropyl; z is 0 or 1; and R³is selected from F, methyl (CH₃) or trifluoromethyl (CF₃).

In yet a highly preferred embodiment of the invention, X is selectedfrom Cl, Br, I, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are O; R¹ and R² areindependently selected from C₁-C₂ alkyl; z is 0 or 1; and R³ is selectedfrom F, methyl (CH₃) or trifluoromethyl (CF₃).

In yet a highly preferred embodiment of the invention, X is selectedfrom Cl, Br, I, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are independentlyselected from O or S; R¹ and R² are independently selected C₁-C₂ alkyl;z is 0 or 1; and R³ is selected from F, methyl (CH₃) or trifluoromethyl(CF₃) and wherein the R³ group is present in any of the positionsindicated as (2), (3), (4), (5) or (6) in formula (I) above, preferablyin any of the positions indicated as (2), (3) or (6) in formula (I)above, most preferably in any of the positions indicated as (2) or (3)in formula (I) above.

In a more highly preferred embodiment of the invention, X is selectedfrom Cl, Br, I, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are independentlyselected from O or S; R¹ and R² are independently selected from C₁-C₃alkyl; z is 0 or 1; and R³ is selected from methyl (CH₃) ortrifluoromethyl (CF₃).

In yet a more highly preferred embodiment of the invention, X isselected from Cl, Br, I, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are O; R¹and R² are independently selected from C₁-C₃ alkyl, C₁-C₃ fluoroalkyl; zis 0 or 1; and R³ is selected from F, methyl (CH₃) or trifluoromethyl(CF₃) and wherein the R³ group is present in any of the positionsindicated as (2), (3), (4), (5) or (6) in formula (I) above, preferablyin any of the positions indicated as (2), (3) or (6) in formula (I)above, most preferably in any of the positions indicated as (2) or (3)in formula (I) above.

In yet a more highly preferred embodiment of the invention, X isselected from Cl, Br, I, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are O; R¹and R² are independently selected from C₁-C₂ alkyl or C₁-C₂ fluoroalkyl;z is 0 or 1; and R³ is selected from F, methyl (CH₃) or trifluoromethyl(CF₃) and wherein the R³ group is present in any of the positionsindicated as (2), (3), (4), (5) or (6) in formula (I) above, preferablyin any of the positions indicated as (2), (3) or (6) in formula (I)above, most preferably in any of the positions indicated as (2) or (3)in formula (I) above.

In yet a more highly preferred embodiment of the invention, X isselected from Cl, Br, I, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are O; R¹and R² are independently selected from C₁-C₂ alkyl; z is 0 or 1; and R³is selected from F, methyl (CH₃) or trifluoromethyl (CF₃) and whereinthe R³ group is present in any of the positions indicated as (2), (3),(4), (5) or (6) in formula (I) above, preferably in any of the positionsindicated as (2), (3) or (6) in formula (I) above, most preferably inany of the positions indicated as (2) or (3) in formula (I) above.

In yet a more highly preferred embodiment of the invention, X isselected from Cl, Br, I, CF₃, S—CH₃ or S—CF₃; Y¹ is O and Y² is selectedfrom O or S; R¹ and R² are independently selected from C₁-C₂ alkyl; z is0 or 1, and R³ is/are selected from F, methyl (CH₃) or trifluoromethyl(CF₃).

In yet a more highly preferred embodiment of the invention, X isselected from Cl, Br, I or CF₃; Y¹ and Y² are O; R¹ and R² are methyl(CH₃); z is 0 or 1; R³ is independently selected from F, methyl (CH₃) ortrifluoromethyl (CF₃), most preferably methyl (CH₃) and wherein the R³group is present in any of the positions indicated as (2), (3), (4), (5)or (6) in formula (I) above, preferably in any of the positionsindicated as (2), (3) or (6) in formula (I) above, most preferably inany of the positions indicated as (2) or (3) in formula (I) above.

In yet a more highly preferred embodiment of the invention, X isselected from I or CF₃; Y¹ and Y² are O; R¹ and R² are methyl (CH₃); zis 0 or 1; R³ is selected from methyl (CH₃) or trifluoromethyl (CF₃),most preferably methyl (CH₃) and wherein the R³ group is present in anyof the positions indicated as (2), (3), (4), (5) or (6) in formula (I)above, preferably in any of the positions indicated as (2), (3) or (6)in formula (I) above, most preferably in any of the positions indicatedas (2) or (3) in formula (I) above.

In the most preferred embodiment of the invention, X is CF₃; Y¹ and Y²are O; R¹ and R² are methyl (CH₃) and z is 0.

In any of the above embodiments R⁴ is most preferably selected as H.

Aspect 5—Medical Use of Selective 5-HT_(2A) Agonists

In the fifth aspect, the invention relates to selective 5-HT_(2A)agonists of the general formula (II) or a pharmaceutically acceptablesalt thereof for use as a medicament

wherein:

X is selected from the group consisting of F, Cl, Br, I, CN, S—(C₁-C₅alkyl), S—(C₁-C₅ fluoroalkyl), S—(C₂-C₅ alkenyl), S—(C₂-C₅fluoroalkenyl), S—(C₂-C₅ alkynyl), S—(C₂-C₅ fluoroalkynyl), C₁-C₅ alkyl,C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅ fluoroalkenyl, C₂-C₅ alkynyl andC₂-C₅ fluoroalkynyl;

Y¹ and Y² are independently selected from the group consisting of H, O,S, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and halogen;

R¹ is not present when Y is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

R² is not present when Y² is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

when present, R¹ and R² are independently selected from the groupconsisting of C₁-C₅ alkyl, C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅fluoroalkenyl, C₂-C₅ alkynyl, C₂-C₅ fluoroalkynyl, C₃-C₅ cycloalkyl orC₃-C₅ fluorocycloalkyl;

z denotes the number of R³ groups and is an integer with a value of 0,1, 2, 3 or 4;

R³ is/are independently selected from the group consisting of F, C₁-C₃alkyl, C₁-C₃ fluoroalkyl, C₂-C₃ alkenyl and C₂-C₃ alkynyl;

with the proviso that at least one of Y¹ or Y² are selected as O or S.

In the fifth aspect, Y¹, Y², R¹, R², z, and R³ are selected with thesame preference as in aspects 1 and 2. Thus, the embodiments under theheadings “Substituents Y¹ and Y²”, “Substituents R¹ and R²”, “Number (z)of R³ substituents and preferred positions” and “Type of R³substituent(s)” in aspects 1 and 2 apply equally well to aspect 5.Furthermore, the preferred embodiments in aspects 1, 2 and 4 also applyto aspect 5. In addition, the description under the heading“Stereochemistry” in aspect 2 applies equally to aspect 5.

Substituent X on the Aromatic Ring

For aspects 4, 5 and 6 (i.e. medical use aspects), X also includes CH₃,F, Cl and Br. Thus, in an embodiment of aspects 4, 5 or 6, X is selectedfrom F, Cl, Br, I, CN, S—(C₁-C₅ alkyl), S—(C₁-C₅ fluoroalkyl), C₁-C₅alkyl or C₁-C₅ fluoroalkyl. In a preferred embodiment, X is selectedfrom F, Cl, Br, I, CN, S—(C₁-C₃ alkyl), S—(C₁-C₃ fluoroalkyl), C₁-C₅alkyl or C₁-C₅ fluoroalkyl. In a more preferred embodiment, X isselected from Cl, Br, I, CN, S—CH₃, S—CF₃, C₁-C₃ alkyl or C₁-C₃fluoroalkyl. In yet a more preferred embodiment, X is selected from Cl,Br, I, S—CH₃, S—CF₃, C₁-C₃ alkyl or C₁-C₃ fluoroalkyl. In an even morepreferred embodiment of the invention, X is selected from Cl, Br, I,CF₃, CN, S—CH₃ or S—CF₃. In yet an even more preferred embodiment of theinvention, X is selected from Cl, Br, I, CF₃, S—CH₃ or S—CF₃. In a yetan even more preferred embodiment, X is selected from Cl, Br, I, CF₃, CNor S—CH₃. In a highly preferred embodiment, X is selected from Cl, Br,I, CF₃ or S—CH₃. In another highly preferred embodiment, X is selectedfrom Cl, Br, I, or CF₃. In an even more highly preferred embodiment, Xis selected from Cl, I, or CF₃. In a yet even more highly preferredembodiment, X is selected from I or CF₃. In the most preferredembodiment of the invention, X is selected from CF₃.

Preferred Embodiments

In a preferred embodiment of the invention, X is selected from F, Cl,Br, I, CN, S—(C₁-C₃ alkyl), S—(C₁-C₃ fluoroalkyl), C₁-C₃ alkyl or C₁-C₃fluoroalkyl; Y¹ and Y² are independently selected from O, CH₃, or S; R¹and R² are independently selected from not present (R¹ not present if Yis CH₃, R² not present if Y² is CH₃), C₁-C₃ alkyl, C₁-C₃ fluoroalkyl,C₃-C₅ cycloalkyl; z is 0, 1, 2 or 3; and R³ is/are independentlyselected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl; with the proviso thatat least one of Y¹ or Y² is selected as O or S.

In yet a preferred embodiment of the invention, X is selected from F,Cl, Br, I, CN, S—(C₁-C₃ alkyl), S—(C₁-C₃ fluoroalkyl), C₁-C₃ alkyl orC₁-C₃ fluoroalkyl; Y¹ and Y² are independently selected from H, O, or S;R¹ and R² are independently selected from not present (R¹ not present ifY¹ is H, R² not present if Y² is H), C₁-C₃ alkyl, C₁-C₃ fluoroalkyl orC₃-C₅ cycloalkyl; z is 0, 1, 2 or 3; and R³ is/are independentlyselected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl; with the proviso thatat least one of Y¹ or Y² is selected as O or S.

In yet a preferred embodiment of the invention, X is selected from F,Cl, Br, I, CN, S—(C₁-C₃ alkyl), S—(C₁-C₃ fluoroalkyl), C₁-C₃ alkyl orC₁-C₃ fluoroalkyl; Y¹ and Y² are independently selected from halogen, Oor S; R¹ and R² are independently selected from not present (R¹ notpresent if Y is halogen, R² not present if Y² is halogen), C₁-C₃ alkyl,C₁-C₃ fluoroalkyl, C₃-C₅ cycloalkyl; z is 0, 1, 2 or 3; and R³ is/areindependently selected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl; withthe proviso that at least one of Y or Y² is selected as O or S.

In a preferred embodiment of the invention, X is selected from F, Cl,Br, I, CN, S—CH₃, S—CF₃, C₁-C₃ alkyl or C₁-C₃ fluoroalkyl; Y¹ and Y² areindependently selected from O, CH₃ or S; R¹ and R² are independentlyselected from not present (R¹ not present if Y is CH₃, R² not present ifY² is CH₃), C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₃-C₅ cycloalkyl; z is 0, 1,2 or 3; and R³ is/are independently selected from F, C₁-C₂ alkyl orC₁-C₂ fluoroalkyl; with the proviso that at least one of Y¹ or Y² areselected as O or S.

In yet a preferred embodiment of the invention, X is selected from F,Cl, Br, I, CN, S—CH₃, S—CF₃, C₁-C₃ alkyl or C₁-C₃ fluoroalkyl; Y¹ and Y²are independently selected from H, O or S; R¹ and R² are independentlyselected from not present (R¹ not present if Y¹ is H, R² not present ifY² is H), C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or C₃-C₅ cycloalkyl; z is 0, 1,2 or 3; and R³ is/are independently selected from F, C₁-C₂ alkyl orC₁-C₂ fluoroalkyl; with the proviso that at least one of Y¹ or Y² isselected as O or S.

In yet a preferred embodiment of the invention, X is selected from F,Cl, Br, I, CN, S—CH₃, S—CF₃, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl; Y¹ and Y²are independently selected from halogen, O or S; R¹ and R² areindependently selected from not present (R¹ not present if Y¹ ishalogen, R² not present if Y² is halogen), C₁-C₃ alkyl, C₁-C₃fluoroalkyl or C₃-C₅ cycloalkyl; z is 0, 1, 2 or 3; and R³ is/areindependently selected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl; withthe proviso that at least one of Y¹ or Y² is selected as O or S.

In a more preferred embodiment of the invention, X is selected from Cl,Br, I, CN, S—CH₃, S—CF₃, C₁-C₃ alkyl or C₁-C₃ fluoroalkyl; Y¹ and Y² areindependently selected from O or S; R¹ and R² are independently selectedfrom C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or C₃-C₅ cycloalkyl; z is 0, 1 or 2;and R³ is/are independently selected from F, C₁-C₂ alkyl or C₁-C₂fluoroalkyl.

In an even more preferred embodiment of the invention, X is selectedfrom Cl, Br, I, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are independentlyselected from O or S; R¹ and R² are independently selected from C₁-C₃alkyl, C₁-C₃ fluoroalkyl or C₃-C₅ cycloalkyl; z is 0, 1 or 2; and R³is/are independently selected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl.

In a yet more preferred embodiment of the invention, X is selected fromCl, Br, I, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are independently selectedfrom O or S; R¹ and R² are independently selected from C₁-C₃ alkyl,C₁-C₃ fluoroalkyl or cyclopropyl; z is 0, 1, 2; and R³ is/areindependently selected from F, C₁-C₂ alkyl or C₁-C₂ fluoroalkyl.

In a highly preferred embodiment of the invention, X is selected fromCl, Br, I, CF₃, CN, S—CH₃ or S—CF₃;

Y¹ and Y² are independently selected from O or S; R¹ and R² areindependently selected from C₁-C₃ alkyl, C₁-C₃ fluoroalkyl orcyclopropyl; z is 0, 1 or 2; and R³ is/are independently selected fromF, methyl (CH₃) or trifluoromethyl (CF₃).

In yet another highly preferred embodiment of the invention, X isselected from Cl, Br, I, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² areindependently selected from O or S; R¹ and R² are independently selectedfrom C₁-C₂ alkyl or C₁-C₂ fluoroalkyl; z is 0, 1, 2 or 3; and R³ is/areindependently selected from F, methyl (CH₃) or trifluoromethyl (CF₃).

In yet another highly preferred embodiment of the invention, X isselected from Cl, Br, I, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² areindependently selected from O or S; R¹ and R² are independently selectedfrom C₁-C₂ alkyl or C₁-C₂ fluoroalkyl; z is 0, 1 or 2; and R³ is/areselected from F, methyl (CH₃) or trifluoromethyl (CF₃).

In a more highly preferred embodiment of the invention, X is selectedfrom Cl, Br, I or CF₃; Y¹ and Y² are independently selected from O or S,R¹ and R² are independently selected from C₁-C₂ alkyl or C₁-C₂fluoroalkyl; z is 0, 1 or 2; and R³ is/are selected from F, methyl (CH₃)or trifluoromethyl (CF₃).

In yet a more highly preferred embodiment of the invention, X isselected from Cl, Br, I or CF₃; Y¹ and Y² are independently selectedfrom O or S; R¹ and R² are independently selected from methyl (CH₃) ortrifluoromethyl (CF₃); z is 0, 1 or 2; and R³ is/are selected from F,methyl (CH₃) or trifluoromethyl (CF₃).

In an even more preferred embodiment of the invention, X is selectedfrom Cl, Br, I, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are O; R¹ and R² areindependently selected from C₁-C₃ alkyl, C₁-C₃ fluoroalkyl or C₃-C₅cycloalkyl; z is 0, 1 or 2; and R³ is/are independently selected from F,C₁-C₂ alkyl or C₁-C₂ fluoroalkyl.

In a yet more preferred embodiment of the invention, X is selected fromCl, Br, I, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are O; R¹ and R² areindependently selected from C₁-C₃ alkyl, C₁-C₃ fluoroalkyl orcyclopropyl; z is 0, 1, 2; and R³ is/are independently selected from F,C₁-C₂ alkyl or C₁-C₂ fluoroalkyl.

In a highly preferred embodiment of the invention, X is selected fromCl, Br, I, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are O; R¹ and R² areindependently selected from C₁-C₃ alkyl, C₁-C₃ fluoroalkyl orcyclopropyl; z is 0, 1 or 2; and R³ is/are independently selected fromF, methyl (CH₃) or trifluoromethyl (CF₃).

In yet another highly preferred embodiment of the invention, X isselected from Cl, Br, I, CF₃, CN, S—CH₃ or S—CF₃; Y¹ and Y² are O; R¹and R² are independently selected from C₁-C₂ alkyl or C₁-C₂ fluoroalkyl;z is 0, 1, 2 or 3; and R³ is/are independently selected from F, methyl(CH₃) or trifluoromethyl (CF₃).

In yet another highly preferred embodiment of the invention, X isselected from Cl, Br, I, CF₃, CN, S—CH₃, S—CF₃; Y¹ and Y² are O; R¹ andR² are independently selected from C₁-C₂ alkyl or C₁-C₂ fluoroalkyl; zis 0, 1 or 2; and R³ is/are selected from F, methyl (CH₃) ortrifluoromethyl (CF₃).

In a more highly preferred embodiment of the invention, X is selectedfrom Cl, Br, I or CF₃; Y¹ and Y² are O; R¹ and R² are independentlyselected from C₁-C₂ alkyl or C₁-C₂ fluoroalkyl; z is 0, 1 or 2; and R³is/are selected from F, methyl (CH₃) or trifluoromethyl (CF₃).

In yet a more highly preferred embodiment of the invention, X isselected from Cl, Br, I or CF₃; Y¹ and Y² are O; R¹ and R² areindependently selected from methyl (CH₃) or trifluoromethyl (CF₃); z is0, 1 or 2; and R³ is/are selected from F, methyl (CH₃) ortrifluoromethyl (CF₃).

In yet a more highly preferred embodiment of the invention, X isselected from Cl, Br, I or CF₃; Y¹ and Y² are O; R¹ and R² are methyl(CH₃); z is 0, 1 or 2; and R³ is/are selected from F, methyl (CH₃) ortrifluoromethyl (CF₃).

In yet a more highly preferred embodiment of the invention, X isselected from I or CF₃; Y¹ and Y² are O; R¹ and R² are methyl (CH₃); zis 0, 1 or 2; and R³ is/are selected from F, methyl (CH₃) ortrifluoromethyl (CF₃).

In yet a more highly preferred embodiment of the invention, X isselected from I or CF₃; Y¹ and Y² are O; R¹ and R² are methyl (CH₃); zis 0, 1 or 2; and R³ is/are selected from F or methyl (CH₃).

In the most preferred embodiment of the invention, X is CF₃; Y¹ and Y²are O, R¹ and R² are methyl (CH₃); and z is 0.

Furthermore, any preferred embodiments mentioned under aspects 1, 2 or 4apply equally well to aspect 5.

Aspect 6—Medical Use of 5-HT_(2A)/5-HT_(2C) Agonists

In the sixth aspect, the invention relates to 5-HT_(2A)/5-HT_(2C)agonists of the general formula (III) or a pharmaceutically acceptablesalt thereof for use as a medicament

wherein:

X is selected from the group consisting of F, Cl, Br, I, CN, S—(C₁-C₅alkyl), S—(C₁-C₅ fluoroalkyl), S—(C₂-C₅ alkenyl), S—(C₂-C₅fluoroalkenyl), S—(C₂-C₅ alkynyl), S—(C₂-C₅ fluoroalkynyl), C₁-C₅ alkyl,C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅ fluoroalkenyl, C₂-C₅ alkynyl,and C₂-C₅ fluoroalkynyl;

Y¹ and Y² are independently selected from the group consisting of H, O,S, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and halogen;

R¹ is not present when Y is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

R² is not present when Y² is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

when present, R¹ and R² are independently selected from the groupconsisting of C₁-C₅ alkyl, C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅fluoroalkenyl, C₂-C₅ alkynyl, C₂-C₅ fluoroalkynyl, C₃-C₅ cycloalkyl andC₃-C₅ fluorocycloalkyl;

* denotes the (R) or (S) stereoisomer or any mixture thereof if a chiralcenter is present;

n is an integer with a value of 1, 2, 3 or 4 to form an azetidine,pyrrolidine, piperidine or azepane ring system;

z denotes the number of R³ groups and is an integer with a value of 0,1, 2, 3 or 4;

R³ is/are independently selected from the group consisting of F, C₁-C₃alkyl, C₁-C₃ fluoroalkyl, C₂-C₃ alkenyl and C₂-C₃ alkynyl;

R⁴ is selected from H or CH₃;

with the proviso that when n=3, * denotes the (R) stereoisomer andfurther with the proviso that at least one of Y¹ or Y² are selected as Oor S.

In the sixth aspect, Y¹, Y², R¹, R², z, R³ are selected with the samepreference as in aspects 1, 2 and 3. Thus, the embodiments under theheadings “Substituents Y¹ and Y²”, “Substituent R¹ and R²”, “Number (z)of R³ substituents” and “Type of R³ substituent(s)” in aspects 1 and 2apply equally to aspect 6. Furthermore, in the sixth aspect, X isselected with the same preference as in aspects 4 and 5. Thus, theembodiments under the heading “Substituent X” in aspects 4 and 5 applyequally to aspect 6. In addition the description under the heading“Stereochemistry” in aspect 3 apply equally to aspect 6. Finally, thepreferred embodiments described under aspects 1-5 apply equally toaspect 6 for all the ring systems (i.e. the azetidine, pyrrolidine,piperidine or azepane ring system). Most preferably, R⁴ is selected as Hin any of the embodiments.

Aspect 7—Synthesis of Compounds According to the Invention

The compounds according to aspect 3 or 6 comprising an azetidine orpyrrolidine were synthesized by a metal free reductive cross-couplingbetween a boronic acid and a diazo compound (generated in situ fromarylsulfonylhydrazones) as illustrated in reaction scheme 1 below. Thearylhydrazones was prepared by condensation between thearylsulfonylhydrazide and the appropriate 3-oxo-heterocycle. A largeamount of aryl boronic acids are commercially available or may beprepared from aryl halides using conventional chemistry, such as e.g.halogen metal exchange followed by quenching with a borate orcross-coupling reactions between an aryl halide with e.g.bis(pinacolato)diboron in the presence of transition metal catalysis.Likewise, heterocycles comprising the ketone such as azetidin-3-one,pyrrolidin-3-one, piperidin-3-one or azepan-3-one are commerciallyavailable or may be prepared in few steps using conventional chemistry.

The compounds according to aspects 1-6 comprising a piperidine wassynthesized readily using e.g. an appropriate cross-coupling reactionsuch as a Suzuki-cross coupling between a 3-halo-pyridine and an arylboronic acid or vice versa (i.e. a pyridine-3-yl boronic acid and anaryl halide). The pyridine in the cross-coupling product maysubsequently be reduced to the piperidine by hydrogenation using anappropriate catalyst such as Adams catalyst (PtO₂). Reaction scheme 2below illustrates one way of synthesizing compounds comprising apiperidine according to aspects 1-6 of the invention using a3-halo-pyridine and a boronic acid.

The substituent X may be present in the boronic acid building blockduring the cross-coupling if it does not interfere with thechemoselectivity of the reaction and tolerates hydrogenation oralternatively, the desired X may be installed subsequently by e.g.electrophilic aromatic substitution (halogenation), optionally followedby further reactions, e.g. a Ullmann type cross-coupling with analkylthiol or a Rosenmund-von Braun reaction.

A large amount of substituted 3-halo-pyridines and substituted arylhalides as building blocks are commercially available and may be useddirectly. Alternatively, such building blocks may be prepared fromcommercially available building blocks in few steps using conventionalchemistry well known to the skilled person. Such chemistry may includee.g. electrophilic aromatic substitutions, S_(N)AR, cross-couplings,halogen-metal exchange and Sandmeyer chemistry etc. Likewise, a largeamount of aryl boronic acids are commercially available or may beprepared from aryl halides using conventional chemistry such as e.g.halogen metal exchange and quenching with a borate or cross-couplingreactions with e.g. bis(pinacolato)diboron.

Aspect 8—Medical Use of Compounds According to the Invention

The compounds according to the invention are for use as a medicament,more particularly for use in the treatment of a depressive disorder. Thedepressive disorder may be selected from a list consisting of majordepressive disorder (MDD) (also known as clinical depression, unipolardepression), treatment resistant depression disorder (TRD), severetreatment resistant depression disorder, melancholia, psychoticdepression, antenatal depression, postnatal depression, bipolardisorder, bipolar type I disorder, bipolar type II disorder, cyclothymicdisorder, dysthymic disorder or seasonal affective disorder. In a highlypreferred embodiment of the invention, the compounds according to theinvention are for use in the treatment of TRD or severetreatment-resistant depression in any of the above depressive disorders.In another highly preferred embodiment of the invention, the compoundsaccording to the invention are for use in the treatment of MDD,treatment-resistant depression disorder (TRD), or severetreatment-resistant depression disorder. In the most preferredembodiment, the compounds according to the invention are for use in thetreatment of MDD or TRD in MDD.

Furthermore, 5-HT_(2A) agonists, such as psilocybin, have shown to beuseful in the treatment of a number of diseases, disorders andaddictions besides the above depressive disorders. Thus, in anotherpreferred embodiment the compounds according to aspects 4-6 are for usein the treatment of a disease, a disorder, an addiction or an abuseselected from the list consisting of Alzheimer's disease, Parkinson'sdisease, autism, general anxiety, existential anxiety, end of lifeanxiety, terminal cancer related end of life anxiety, epilepsy,sleep-wake disorders, neurocognitive disorders, obsessive compulsivedisorder (OCD), attention deficit disorder (ADD), attention deficithyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD),stress, acute stress disorder, Horton's headache, chronic clusterheadache, migraine, general local inflammation, muscle inflammation,joint inflammation, pulmonary inflammation, asthma, arthritis, smokingcessation, alcohol cessation, cocaine cessation, heroin cessation,opioid cessation, methamphetamine cessation, general addiction therapy,eating disorders such as compulsive eating disorders, anorexia nervosa,bulimia nervosa, binge eating disorder, Pica, Rumination disorder,avoidant/restrictive food intake disorder, night eating syndrome, otherspecified feeding or eating disorder (OSFED), body dysmorphic disorder,purging disorder, pain, chronic pain disorders, sleep wake disorders orphysical rehabilitation. In a highly preferred embodiment, the compoundsaccording to the aspects 4-6 are for use in the treatment of chroniccluster headache, bipolar type II disorder, body dysmorphic disorder.

The results in FIGS. 4A and 4B demonstrate the effect compound 8 inrodent models for depression and treatment-resistant depression. Thus,in a highly preferred embodiment, the invention relates to the use ofselective 5-HT_(2A) agonists of aspect 3 for use in the treatment oftreatment-resistant depression in any depressive disorder, mostpreferably MDD. Thus, the compounds of the invention are particularlyintended for use in the treatment of an individual who does not respondadequately to current anti-depressive treatments, such as SSRIs. In oneembodiment of the invention, the treatment of treatment-resistantdepression may involve an initial co-administration of a compoundaccording to the present invention as a rapid-acting antidepressant tocircumvent the slow on-set of the SSRIs. In another embodiment of theinvention, the treatment of treatment-resistant depression may involvesubstitution of an antidepressant with a compound according to thepresent invention.

Aspect 9—Pharmaceutical Compositions

Another aspect of the invention relates to a pharmaceutical compositioncomprising a compound according to aspects 1-6 of the invention, apharmaceutical acceptable carrier and optionally one or morepharmaceutically acceptable excipients. In the present context, apharmaceutical composition should be understood as any conventional typeof formulation intended for e.g. parental, oral, inhalation or topicaladministration. Parental formulations may be intended for intravenous,subcutaneous or intramuscular administration. Suitable oral formulationsmay include tablets, capsules, powders, solutions, suspensions or asustained release formulation for oral administration. Other suitableformulations may include creams, ointments, gels, pastes or patches fortopical administration. Suitable parental formulations may includeliquids, lyophilized or spray dried powders for dissolution prior toparental administration. Preferably, the formulation is an oralformulation such as a tablet or a parental formulation such as a liquid.The skilled person is familiar with the manufacture of different typesof formulations and suitable excipients to use in the differentformulation types can be found in e.g. Handbook of PharmaceuticalExcipients. In a pharmaceutical composition, comprising a compoundaccording to aspects 2 or 4 of the invention, the (S)-stereoisomershould preferably be present in at least 80% ee, such as 85% ee, such90% ee, such as 95% ee, such as 96% ee, preferably 97% ee, morepreferably 98% ee, even more preferably at least 99% ee, most preferablyonly the (S)-stereoisomer.

Pharmaceutically Acceptable Salts

Any of the compounds according to the invention, exemplified with thelist of compounds 1-57, may be in the form of a pharmaceuticallyacceptable salt since they all comprise a basic moiety (i.e. a secondaryamine in the azetidine, pyrrolidine, piperidine or azepane). Thus, thecompound may be in the form of a pharmaceutically acceptable acidaddition salt. The salts may be either amorphous or crystalline productsand a salt may exist as different polymorphs. The skilled person isaware of a large number of acids suitable for formation of apharmaceutically acceptable salt as can be found in e.g. Handbook ofPharmaceutical Salts. Typical, pharmaceutical acceptable acid additionsalts may be formed between a compound according to the invention and anacid selected from group consisting of but not limited to e.g. aceticacid, aspartic acid, benzenesulfonic acid, benzoic acid, carbonic acid,camphorsulfonic acid, HCl, HBr, HI, citric acid, decanoic acid,ethylenediaminetetraacetic acid, gluconic acid, fumaric acid, lacticacid, maleic acid, malic acid, methanesulfonic acid, nitric acid,phosphoric acid, propionic acid, tartaric acid, tosylic acid, sulfuricacid, salicylic acid or succinic acid. The skilled person is well awareof the importance of pharmaceutical salts. Salt screens are thereforeoften performed to identify suitable crystalline products withadvantageous properties. Different salts or crystal forms of the productmay influence the physiochemical properties of the compound. Thus, saltsmay have influence on e.g. the chemical and physical stability,hygroscopicity, melting point, solubility, dissolution rate andbioavailability. Thus, in the present context, a pharmaceuticallyacceptable salt is intended to include all suitable acid addition saltsin both amorphous and crystalline forms as well as different polymorphsthereof.

Combination Therapy

The compounds according to the present invention may be used alone (i.e.in mono-therapy) or in combination with one or more knownanti-depressants (i.e. in combination therapy). Thus, combinationtherapy may include but are not limited to combinations with othertherapeutically active ingredients such as SSRIs, SNRIs, NDRIs, TCAs,benzodiazepines, atypical antipsychotics, stimulants such asamphetamines and methylphenidate, ketamine, classical psychedelics suchas mescaline, lysergic acid diethylamide (LSD), psilocybin andN,N-dimethyltryptamine (DMT). In case of combination therapy the othertherapeutically active ingredients may be administered in separatedosage forms or as a single dosage form comprising one or more compoundsaccording to the invention in combination with one or more othertherapeutically active ingredients. In particular, due to the slowon-set of e.g. SSRI as described above, it might be beneficial in someinstances to initiate the treatment with one or more compounds accordingto the invention together with or followed by e.g. a SSRI to avoid anydelay in anti-depressant effect.

Examples

In Vitro Pharmacology General Information

The Ca²⁺/Fluo-4 Assay

The functional properties of the compounds were characterised at stableHEK293 cell lines stably expressing the human 5-HT_(2A) receptor orhuman 5-HT_(2C) receptor in the Ca²⁺/Fluo-4 assay essentially aspreviously described.¹⁰ Briefly, the cells were split intopoly-D-lysine-coated black 96-well plates with clear bottoms (6×10⁴cells/well). The following day the culture medium was aspirated and thecells were incubated in 50 μl assay buffer [Hanks Buffered SalineSolution containing 20 mM HEPES, 1 mM CaCl₂, 1 mM MgC₂, 2.5 mMprobenecid, pH 7.4] supplemented with 6 mM Fluo-4/AM at 37° C. for 1hour. Next, the buffer was aspirated, the cells were washed once with100 μl assay buffer, and then 100 μl assay buffer was added to the cells(in the antagonist experiments the compound was added at this point).The 96-well plate was assayed in FLEXStation³ Plate Reader (MolecularDevices, Crawley, United Kingdom) measuring emission (in fluorescenceunits) at 525 nm caused by excitation at 485 nm before and up to 90seconds after addition of 33.3 μl test compound solution in the assaybuffer. The compounds were characterized in duplicate at least threetimes at each cell line. In the antagonist tests, 5-HT (EC₈₀) was usedas agonist.

TABLE 1a

5-HT_(2A) 5-HT_(2C) Selectivity Compound EC₅₀ (nM) R_(max) ± EC₅₀ (nM)R_(max) ± EC₅₀ ^(5-HT2C)/ No. * X R¹ R² Y¹ Y² R³ [pEC₅₀ ± S.E.M.] S.E.M.[pEC₅₀ ± S.E.M.] S.E.M EC₅₀ ^(5-HT2A)  7 (R) CF₃ Me Me O O —   150 65 ±5     860 26 ± 2 5.7 [6.82 ± 0.04] [6.07 ± 0.06]  8 (S) CF₃ Me Me O O —  21 47 ± 3  n.a. [@ 50 μM] ^(a) n.d. ^(d) >1,000 ^(e) [7.67 ±0.05] >50,000 [<4.3]  9 (R) Cl Me Me O O —   690 61 ± 2   1,800 26 ± 22.6 [6.16 ± 0.11] [5.75 ± 0.04] 10 (S) Cl Me Me O O —   66 32 ± 6  n.a.[@ 50 μM] ^(a) n.d. ^(d) >1,000 ^(e) [7.18 ± 0.05] >50,000 [<4.3] 11 (R)Br Me Me O O —   370 67 ± 6   1,900 34 ± 4 5.1 [6.43 ± 0.11] >50,000[<4.3] 12 (S) Br Me Me O O —   69 37 ± 4  n.a. [@ 50 μM] ^(a) n.d.^(d) >1,000 ^(e) [7.16 ± 0.10] >50,000 [<4.3] 13 (R) I Me Me O O —   26058 ± 4   2,800 20 ± 2 11 [6.58 ± 0.03] [5.55 ± 0.08] 14 (S) I Me Me O O—   37 53 ± 3  n.a. [@ 50 μM] ^(a) n.d. ^(d) >1,000 ^(e) [7.43 ±0.02] >50,000 [<4.3] 15 (R) CN Me Me O O — 2,200 41 ± 6  ~10,000 ~13-17^(c) 4.5 [5.66 ± 0.06] [~5.0] ^(c) 16 (S) CN Me Me O O —   270 25 ± 4 n.a. [@ 50 μM] ^(a) n.d. ^(d)   >200 ^(e) [6.56 ± 0.13] >50,000 [<4.3]17 (R) SMe Me Me O O —   180 85 ± 7   2,300 38 ± 5 13 [6.75 ± 0.06][5.63 ± 0.03] 18 (S) SMe Me Me O O —   26 84 ± 6     510 16 ± 2 20 [7.59± 0.11] [6.29 ± 0.06] 19 (R) CF₃ Me Et O O —   320 86 ± 6  w.a. n.d.^(d)   >30 ^(e) [6.50 ± 0.10 ] [@ 2-10-50 μM] ^(b) 20 (S) CF₃ Me Et O O—   10 95 ± 1     290 44 ± 5 28 [7.99 ± 0.11] [6.54 ± 0.04] 21 (R) CF₃Et Et O O — 3,000 69 ± 4  w.a. n.d. ^(d)   >10 ^(e) [5.52 ± 0.06] [@10-50 μM] ^(b) 22 (S) CF₃ Et Et O O —   100 47 ± 6  w.a. n.d. ^(d)  >300 ^(e) [6.99 ± 0.07] [@ 10-50 μM] ^(b) 23 (R) Me Me Me O O —   26089 ± 4   1,200 53 ± 6 4.6 [6.58 ± 0.06] [5.92 ± 0.08] 24 (S) Me Me Me OO —   100 75 ± 3  w.a. n.d. ^(d)   >300 ^(e) [6.98 ± 0.10] [@ 10-50 μM]^(b) 25 (R) iPrS Me Me O O —   290 91 ± 4   2,300 50 ± 1 8.0 [6.54 ±0.09] [5.46 ± 0.05] 26 (S) iPrS Me Me O O —   160 92 ± 4  w.a. n.d. ^(d)  >30 ^(e) [6.81 ± 0.09] [@ 2-10-50 μM] ^(b) 27 (R) SEt Me Me O O —  190 83 ± 6     780 52 ± 5 4.1 [6.73 ± 0.10] [6.11 ± 0.08] 28 (S) SEtMe Me O O —   38 80 ± 6     570  8 ± 2 15 [7.42 ± 0.09] [6.25 ± 0.08] 29(R) CF₃ Et Me O O —   410 77 ± 7   2,700 34 ± 1 6.7 [6.39 ± 0.08] [5.56± 0.02] 30 (S) CF₃ Et Me O O —   38 40 ± 3  w.a. [@ 50 μM] ^(b) n.d.^(d) >1,000 ^(e) [7.42 ± 0.10] 31 (R) Et Me Me O O —   110 93 ± 5    640 44 ± 5 5.6 [6.94 ± 0.09] [6.19 ± 0.12] 32 (S) Et Me Me O O —   4179 ± 4     380 20 ± 4 9.3 [7.39 ± 0.11] [6.42 ± 0.12] 33 (R) Et Me Et OO — 1,100 89 ± 4  w.a. n.d. ^(d)   >10 ^(e) [5.95 ± 0.11] [@ 2-10-50 μM]^(b) 34 (S) Et Me Et O O —   52 88 ± 4     840 28 ± 4 16 [7.29 ± 0.08][6.08 ± 0.02] 35 — CF₃ Me Me O O 6′-   73 75 ± 4   3,000 21 ± 2 41 Me[7.14 ± 0.11] [5.53 ± 0.10] 36 — CF₃ Me Me O O 3′-   48 68 ± 2     40043 ± 6 8.2 Me [7.32 ± 0.10] [6.40 ± 0.09] 37 — CF₃ Me Me O O 2′-   27090 ± 10  3,400 33 ± 5 13 Me [6.58 ± 0.11] [5.47 ± 0.09] 38 — CF₃ Me Me OO 2′-   160 38 ± 4  w.a. n.d. ^(d)   >300 ^(e) Me [6.81 ± 0.09 ] [@ 50μM] ^(b) 39 (S) CF₃ CH₂F Me O O —   150 40 ± 5  w.a. n.d. ^(d)   >300^(e) [6.82 ± 0.12] [@ 50 μM] ^(b) 40 (R) Et Et Et O O — ~7,000-10,000~61-74 ^(c) w.a. n.d. ^(d)    >3 ^(e) [~5.15-5.00] ^(c) [@ 10-50 μM]^(b) 41 (S) Et Et Et O O —   380 44 ± 5  w.a. n.d. ^(d)   >100 ^(e)[6.42 ± 0.09] [@ 50 μM] ^(b) 42 (R) Et Et Me O O — 1,500 80 ± 9  w.a.n.d. ^(d)   >10 ^(e) [5.82 ± 0.07] [@ 2-10-50 μM] ^(b) 43 (S) Et Et Me OO —   140 42 ± 6  n.a. [@ 50 μM] ^(a) n.d. ^(d) >1,000 ^(e) [6.86 ±0.11] >50,000 [<4.3] 44 (R) CF₃ Me Me S O —   71 96 ± 6     660 50 ± 29.3 [7.15 ± 0.11] [6.18 ± 0.12] 45 (S) CF₃ Me Me S O —  9.1 82 ± 3    170 22 ± 4 18 [8.04 ± 0.02] [6.78 ± 0.13] 46 (R) CF₃ Me Et S O —  150 97 ± 2   1,100 53 ± 5 7.4 [6.84 ± 0.05] [5.97 ± 0.05] 47 (S) CF₃Me Et S O —   26 96 ± 3     450 43 ± 6 17 [7.58 ± 0.11] [6.34 ± 0.03] 48(R) CF₃ — Me H O — 1,800 68 ± 7  w.a. n.d. ^(d)   >50 ^(e) [5.74 ± 0.09][@ 50 μM] ^(b) 49 (S) CF₃ — Me H O — 2,500 65 ± 3   1,300 35 ± 3 0.51[5.61 ± 0.07] [5.90 ± 0.10] 50 (R) CF₃ Me — O F —   640 78 ± 6   1,80040 ± 8 2.8 [6.19 ± 0.10] [5.75 ± 0.03] 51 (S) CF₃ Me — O F —   140 79 ±5  w.a. n.d. ^(d)   >100 ^(e) [6.85 ± 0.08] [@ 10-50 μM] ^(b) 52 (R) CF₃Me — O H —   480 77 ± 2   1,400 38 ± 6 3.0 [6.32 ± 0.12] [5.85 ± 0.05]53 (S) CF₃ Me — O H —   69 68 ± 2  w.a. n.d. ^(d)   >100 ^(e) [7.16 ±0.05] [@ 2-10-50 μM] ^(b) 54 (R) CF₃ Cyclo Me O O — 1,800 76 ± 4 ~3,000~10,000 ~46-63 ^(c) ~1.7-~5.6 propyl [5.75 ± 0.10] [~5.52-5.00]^(c) 55 (S) CF₃ Cyclo Me O O — 1,100 30 ± 5  w.a. n.d. ^(d)   >50 ^(e)propyl [5.97 ± 0.06] [@ 50 μM] ^(b) 56 (R) n- Me Me O O —   340 93 ± 5  1,600 68 ± 6 4.6 Bu [6.46 ± 0.05] [5.80 ± 0.07] 57 (S) n- Me Me O O —  270 82 ± 2  w.a. n.d. ^(d)   >30 ^(e) Bu [6.57 ± 0.06] [@ 2-10-50 μM]^(b)

5-HT_(2A) 5-HT_(2C) Selectivity Compound EC₅₀ (nM) R_(max) ± EC₅₀ (nM)R_(max) ± EC₅₀ ^(5-HT2C)/ No. * X R¹ R² Y¹ Y² R⁴ [pEC₅₀ ± S.E.M.] S.E.M.[pEC₅₀ ± S.E.M.] S.E.M. EC₅₀ ^(5-HT2A) 58 (R) CF₃ Me Me O O Et w.a. [@2-10-50 n.d. ^(d) w.a. n.d. ^(d) n.d. ^(d) μM] ^(b) [@ 2-10-50 μM] ^(b)59 (S) CF₃ Me Me O O Et 1,500 44 ± 3  w.a. n.d. ^(d)   >30 ^(e) [5.82 ±0.09] [@ 10-50 μM] ^(b) 60 (R) CF₃ Me Me O O Me 1,100 53 ± 8  w.a. n.d.^(d)    >5 ^(e) [5.96 ± 0.09] [@ 2-10-50 μM] ^(b) 61 (S) CF₃ Me Me O OMe   390 19 ± 2     920 14 ± 2 2.2 [6.40 ± 0.07] [6.04 ± 0.03]

  480 [6.32 ± 0.11] 87 ± 4   2,000 [5.71 ± 0.03] 82 ± 3 4.1 (8a)

w.a. [@ 10-50 μM] n.d. ^(d) w.a. [@ 10-50 μM] n.d. ^(d) n.d. ^(d) (8b)

 0.44 [9.36 ± 0.06] 88 ± 7    3.4 [8.47 ± 0.08] 83 ± 8 7.8 (DOI)

 0.76 [9.12 ± 0.07] 83 ± 6     47 [7.33 ± 0.10] 96 ± 7 62 (25CN-NBOH)Agonist potencies (EC₅₀ values) and efficacies (maximal responses,R_(max) values) exhibited by the compounds according to the inventionwhen tested at stable h5-HT_(2A)- and h5-HT_(2C)-HEK293 cell lines in aCa²⁺ imaging assay using the calcium fluorophore Fluo-4. EC₅₀ values aregiven in nM with pEC₅₀ values in brackets, and R_(max) values are givenin % as the R_(max) of 5-HT at the respective receptors. The EC₅₀^(5-HT2C)/EC₅₀ ^(5-HT2A) ratios for the compounds are given as a measureof their 5-HT_(2A)-over-5-HT_(2C) selectivity degrees. The compounds areshown in comparison with the reference compounds 8a and 8b from ACSChem. Neurosci. 2013, 4, 96-109 and the N-alkylated analogues 58-61. Thedata are based on 3 or 4 individual experiments for all compoundsperformed at both receptors (n = 3-4). ^(a) n.a., no agonist activity:the compound did not evoke significant responses at concentrations up to50 μM. ^(b) w.a., weak agonist activity: the compound only evokedsignificant response at the indicated concentrations. Thus, a completeconcentration-response curve could not be fitted, and EC₅₀ and R_(max)values could not be determined. ^(c) The agonist concentration-responserelationship exhibited by the compound was not completely saturated at50 μM. Thus, EC₅₀ and R_(max) values were estimated from the fittedcurves and are given as intervals of the values obtained in theindividual experiments. ^(d) n.d., not determinable. ^(e) Since the EC₅₀value at 5-HT_(2C) could not be determined, the EC₅₀ ^(5-HT2C/)EC₅₀^(5-HT2A) ratio given for the compound is a conservative estimate basedon the 5-HT_(2A) EC₅₀ and the sizes of the agonist responses evoked bythe effective concentrations of the compound at 5-HT_(2C). The compoundsaccording to the invention were all 5-HT_(2A) agonists with varyingdegree of potency in the low μM to low nM range. In general, the(S)-enantiomers showed high selectivity towards 5-HT_(2A) over5-HT_(2C), with some (S)-enantiomers not evoking significant agonistresponses in the h5-HT_(2C)-HEK293 cells at concentrations up to 50 μM(exemplified for compound 8 in FIG. 1B).

TABLE 1b

5-HT_(2A) 5-HT_(2C) Selectivity Compound EC₅₀ (nM) R_(max) ± EC₅₀ (nM)R_(max) ± EC₅₀ ^(5-HT2C)/ No. * X N [pEC₅₀ ± S.E.M.] S.E.M [pEC₅₀ ±S.E.M.] S.E.M. EC₅₀ ^(5-HT2A) 1 — Br 1 1.6 [8.80 ± 0.10] 97 ± 3 5.8[8.24 ± 0.07] 90 ± 3 3.6 2 — CF₃ 1 1.0 [9.00 ± 0.10] 95 ± 2 5.2 [8.28 ±0.02] 87 ± 4 5.2 3 (R) Br 2 5.3 [8.11 ± 0.08] 57 ± 3  26 [7.59 ± 0.03]73 ± 3 4.9 4 (S) Br 2 7.7 [8.11 ± 0.08] 39 ± 4  18 [7.75 ± 0.08] 16 ± 32.3 5 (R) CF₃ 2  11 [7.98 ± 0.08] 45 ± 1  41 [7.39 ± 0.08] 65 ± 4 3.7 6(S) CF₃ 2 5.4 [8.27 ± 0.09] 35 ± 4  19 [7.72 ± 0.06] 28 ± 2 3.5 Agonistpotency (EC₅₀) and efficacy (R_(max)) of compounds according to theinvention when tested at stable h5-HT_(2A)- and h5-HT_(2C)-HEK293 celllines in a Ca²⁺ imaging assay using the calcium fluorophore Fluo-4. EC₅₀values are given in nM with pEC₅₀ values in brackets, and R_(max) valuesare given in % as the R_(max) of 5-HT at the respective receptors. Thedata are based on 3-4 experiments for all compounds at both receptors (n= 3-4).

The functional properties of compound 8 were characterized in a cellline stably expressing the human 5-HT_(2B) receptor in a similarfluorescence-based Ca²⁺ imaging assay (performed by Eurofins). Briefly,the cell line was expanded from a freezer stock according to standardprocedures. Cells were seeded in a total volume of 20 μL intoblack-walled, clear-bottom, Poly-D-lysine coated 384-well microplatesand incubated at 37° C. for the appropriate time prior to testing. Theassay was performed in 1×Dye Loading Buffer consisting of 1×Dye,1×Additive A and 2.5 mM Probenecid in HBSS/20 mM HEPES (pH 7.4). Cellswere loaded with dye prior to testing. Media was aspirated from cellsand replaced with 20 μL Dye Loading Buffer, and the cells were incubatedfor 30-60 minutes at 37° C. After dye loading, cells were removed fromthe incubator and 10 μL HBSS/20 mM HEPES was added. Cells were incubatedfor 30 minutes at room temperature in the dark to equilibrate platetemperature. Intermediate dilution of sample stocks was performed togenerate 4×sample in assay buffer. Compound agonist activity wasmeasured on a FLIPR Tetra (MDS). Calcium mobilization was monitored for2 minutes and 10 μL 4×sample in HBSS/20 mM HEPES was added to the cells5 seconds into the assay.

TABLE 2

5-HT_(2A) 5-HT_(2B) Selectivity Com. EC₅₀ (nM) R_(max) ± EC₅₀ ^(5HT2B)/No. * X n [pEC₅₀ ± S.E.M.] S.E.M. EC₅₀ (nM) R_(max) EC₅₀ ^(5-HT2A) 10(S) CF₃ 3 21 47 ± 3 280 84 13 [7.67 ± 0.05] Agonist potency (EC₅₀) andefficacy (R_(max)) of compound 8 according to the invention when testedat a stable h5-HT_(2B) cell line in a fluorescence-based Ca²⁺ imagingassay (performed by Eurofins). The EC₅₀ value is given in nM, and theR_(max) value is given in % as the R_(max) of 5-HT at the receptor. Thepharmacological data for compound 8 at the 5-HT_(2A)-HEK293 cell line(from Table 1a) is given for comparison.

The IP Assay

The agonist properties of the compounds were characterized at HEK293cell lines expressing the human 5-HT_(2A), human 5-HT_(2B) or human5-HT_(2C) receptors in an IP assay essentially as previouslydescribed.¹⁹ The testing was performed by Eurofins. In the assay, theagonist activity of the compound at the receptors is investigated bymeasuring its effect on IP1 production in the cell using the HomogeneousTime Resolved Fluorescence (HTRF) detection method. Briefly, on the dayof the assay the cells were suspended in a buffer containing 10 mMHepes/NaOH (pH 7.4), 4.2 mM KCl, 146 mM NaCl, 1 mM CaCl₂, 0.5 mMMgCl₂,5.5 mM glucose and 50 mM LiCl, then distributed in microplates at adensity of 1.5×10⁴ cells/well and incubated for 30 min at 37° C. in thepresence of buffer (basal control), test compound or reference agonist.Separate assay wells containing 1 μM 5-HT (5-HT_(2B) and 5-HT_(2C)) or10 μM 5-HT (5-HT_(2A)) for stimulated control measurements wereincluded. Following incubation, the cells were lysed, and thefluorescence acceptor (D2-labeled IP1) and fluorescence donor (anti-IP1antibody labeled with europium cryptate) were added. After 60 min atroom temperature, the fluorescence transfer was measured at λ_(ex)=337nm and λ_(em)=620 and 665 nm using a microplate reader (Envision, PerkinElmer). The test compounds were characterized in eight differentconcentrations in duplicate at each of the three cell lines. Thereference agonist 5-HT was tested in each experiment. The IP1concentrations in the different wells were determined by dividing thesignal measured at 665 nm by that measured at 620 nm (ratio). The datafor the test compounds were expressed as a percent of the controlresponse to the 5-HT R_(max).

TABLE 3

5-HT_(2A) 5-HT_(2B) Selectivity Compound EC₅₀ ^(5-HT2B)/ No. * X R¹ R²Y¹ Y² R³ EC₅₀ (nM) R_(max) EC₅₀ (nM) R_(max) EC₅₀ ^(5-HT2A)  8 (S) CF₃Me Me O O — 20 74 150 60 7.5 10 (S) Cl Me Me O O — 380 62 240 50 0.63 12(S) Br Me Me O O — 250 70 190 48 0.76 14 (S) I Me Me O O — 45 72 170 573.8 16 (S) CN Me Me O O — 980 77 5,000 45 5.1 18 (S) SMe Me Me O O — 27072 180 64 0.67 20 (S) CF₃ Me Et O O — 36 79 580 57 16 22 (S) CF₃ Et Et OO — 170 54 n.a. [@ 100 μM] ^(a) n.d. ^(b) >1,000 ^(c) 24 (S) Me Me Me OO — 560 67 360 38 0.64 26 (S) iPrS Me Me O O — 1,100 72 1,200 43 1.1 28(S) SEt Me Me O O — 180 62 240 55 1.3 30 (S) CF₃ Et Me O O — 140 351,200 26 8.6 32 (S) Et Me Me O O — 110 85 280 54 2.5 34 (S) Et Me Et O O— 160 78 860 50 5.4 35 — CF₃ Me Me O O 6′- 260 70 850 28 3.3 Me 36 — CF₃Me Me O O 3′- 41 61 120 39 2.9 Me 37 — CF₃ Me Me O O 2′- 1,500 110 62054 0.4 Me 38 — CF₃ Me Me O O 2′- 120 60 2200 29 18 Me 39 (S) CF₃ CH₂F MeO O — 300 60 1,100 54 3.6 41 (S) Et Et Et O O — 720 62 n.a. [@ 100 μM]^(a) n.d. ^(b)   >100 ^(c) >100,000 43 (S) Et Et Me O O — 670 45 1,10011 1.6 45 (S) CF₃ Me Me S O — 14 71 92 63 6.6 47 (S) CF₃ Me Et S O — 13095 620 49 4.8 51 (S) CF₃ Me — O F — 260 59 740 37 2.8 53 (S) CF₃ Me — OH — 250 87 940 51 3.8 55 (S) CF₃ Cyclo Me O O — 3,000 38 n.a. [@ 100 μM]^(a) n.d. ^(b)   >30 ^(c) propyl >100,000 57 (S) n- Me Me O O — 190 62350 18 1.8 Bu Agonist potency (EC₅₀) and efficacy (R_(max)) exhibited byselected compounds according to the invention when tested at human5-HT_(2A) and human 5-HT_(2B) receptors in the Eurofins functional IPassay. EC₅₀ (in nM) and R_(max) (in % of R_(max) of 5-HT at therespective receptors) are based on duplicate determinations. The EC₅₀^(5-HT2B)/EC₅₀ ^(5-HT2A) ratios for the compounds are given as a measureof their 5-HT_(2A)-over-5-HT_(2B) selectivity degrees. ^(a) n.a., noagonist activity: the compound did not evoke significant responses atconcentrations up to 100 μM. ^(b) n.d., not determinable. ^(c) Since theEC₅₀ value at 5-HT_(2B) could not be determined, the EC₅₀ ^(5-HT2B)/EC₅₀^(5-HT2A) ratio given for the compound is a conservative estimate basedon its 5- HT_(2A) EC₅₀ and the lack of significant agonist response at5-HT_(2B) at 100 μM. As can be seen from table 3 the majority ofcompounds showed selectivity towards 5-HT_(2A) over 5-HT_(2B).

TABLE 4 5-HT_(2A) 5-HT_(2B) 5-HT_(2C) Selectivity R_(max) R_(max)R_(max) EC₅₀ ^(5-HT2C)/ EC₅₀ (nM) (%) EC₅₀ (nM) (%) EC₅₀ (nM) (%) EC₅₀^(5-HT2A)

   7.1 78     81 81    3.8 100 0.53 (2C-TFM)

   7.3 89     13 79    9.1 89 1.3 (DOI)

   7.2 87    320 29     27 84 3.8 (25CN-NBOH)

  2,300 94    770 20    170 80 0.07 (8a)

n.a. [@ 100 μM] ^(a) >100,000 n.d. ^(c) n.a. [@ 100 μM] ^(a) >100,000n.d. ^(c) w.a. [@ 100 μM] ^(b) >100,000 n.d. ^(c) n.d. ^(c) (8b)Functional properties of the known 5HT_(2A) agonists4-trifluoromethyl-2,5-dimethoxyphenethylamine (2C-TFM),2,5-Dimethoxy-4-iodoamphetamine (DOI) and4-(2-((2-hydroxybenzyl)amino)ethyl)-2,5- dimethoxybenzonitrile 25CN-NBOHin comparison with compound 8a and 8b from ACS Chem. Neurosci. 2013, 4,96-109 at human 5-HT_(2A), 5-HT_(2B) and 5-HT_(2C) in the Eurofins IPassay. EC₅₀ (in nM) and R_(max) (in % of R_(max) of 5-HT) are based onduplicate determinations. The EC₅₀ ^(5-HT2C)/EC₅₀ ^(5-HT2A) ratios forthe compounds are given as a measure of their 5-HT_(2A)-over-5-HT_(2C)selectivity degrees. ^(a) n.a., no agonist activity: the compound didnot evoke significant responses at concentrations up to 100 μM. ^(b)w.a., weak agonist activity: the compound only evoked a significantresponse at 100 μM. Thus, a complete concentration-response curve couldnot be fitted, and EC₅₀ and R_(max) values could not be determined. ^(c)n.d., not determinable. As can be seen from table 4 compound 8b does notact as an agonist at 5-HT_(2A), 5-HT_(2B) and 5-HT_(2C). Furthermore,compound 8a is an agonist at 5-HT_(2A) and 5-HT_(2C) but with highselectivity for 5-HT_(2C) over 5-HT_(2A).

Radioligand Binding Assays.

The binding affinities shown in table 5 of psilocin and compound 8 atvarious monoaminergic receptors were determined in radioligandcompetition binding assays by Psychiatric Drug Screening Programaccording to the experimental described in Assay Protocol Book,VersionII.^(11,16) As shown compound 8 shows less affinity for variousmonoaminergic receptors compared to Psilocin.

TABLE 5 Binding affinities (K) exhibited by psilocin and compound 8 atvarious monoaminergic receptors in radioligand binding competitionassays. The binding data for psilocin and compound 8 were determined byPsychiatric Drug Screening Program.¹¹ Psilocin Comp. 8 Psilocin Comp. 8Receptor K_(i) (nM) K_(i) (nM) Receptor K_(i) (nM) K_(i) (nM) 5-HT_(1A)63 330 D1 20 >10,000 5-HT_(1B) 305 n.t. D2 >10,000 >10,000 5-HT_(1D) 19663 D3 100 >10,000 5-HT_(1e) 44 762 D4 >10,000 >10,000 5-HT_(2A) 34016.5 D5 >10,000 >10,000 5-HT_(2B) 4.7 85 α_(1A) >10,000 >10,0005-HT_(2C) 140 42 α_(1B) >10,000 >10,000 5-HT₃ n.t. >10,000 α_(2A) 2,0001,400 5-HT_(5A) 70 >10,000 α_(2B) 1,300 820 5-HT₆ 72 623 α_(2C)4,400 >10,000 5-HT₇ 72 2,360

TABLE 6 Agonist potency (EC₅₀) and efficacy (R_(max)) of psilocin (theactive metabolite of psilocybin) when tested at stable 5-HT_(2A)- and5-HT_(2C)-cell lines and cells transiently transfected with 5-HT_(2B) ina phosphoinositide hydrolysis assay. EC₅₀ ± S.D. values are given in nMand R_(max) ± S.D. values are given in % of the R_(max) of 5-HT at therespective receptors. Data are from Sard, H. et al.¹⁵ Psilocin ReceptorEC₅₀ (nM) R_(max) (%) 5-HT_(2A) 24 ± 2  43 ± 17 5-HT_(2B) 58 455-HT_(2C) 30 ± 18 51 ± 37

In Vivo Pharmacology General Information

The Head Twitch Response model 1 (Mice) Animals.

Male C57BL/6J mice (6-8 weeks old) obtained from Jackson Laboratories(Bar Harbor, Me., USA) were housed in a vivarium at an AAALAC-approvedanimal facility that meets all Federal and State requirements for careand treatment of laboratory animals. Mice were housed up to four percage in a climate-controlled room on a reverse-light cycle (lights on at1900 h, off at 0700 h) and were provided with ad libitum access to foodand water, except during behavioral testing. Testing was conductedbetween 1000 and 1800 h. All animal experiments were carried out inaccordance with NIH guidelines.

Head Twitch Response Studies.

The head twitch response (HTR) was assessed using a head-mounted magnetand a magnetometer detection coil12. Briefly, mice were anesthetized, asmall incision was made in the scalp, and a small neodymium magnet wasattached to the dorsal surface of the cranium using dental cement.Following a two-week recovery period, HTR experiments were carried outin a well-lit room with at least 7 days between sessions to avoidcarryover effects. Compound 8 was dissolved in isotonic saline solution(vehicle) in concentrations of 0.06 mg/mL, 0.2 mg/mL, 0.6 mg/mL, 2 mg/mLand 6 mg/mL and injected intraperiotoneally (IP) at a volume of 5 mL/kg.Mice were injected with compound 8 or vehicle and then HTR activity wasrecorded in a glass cylinder surrounded by a magnetometer coil for 30min. Coil voltage was low-pass filtered (2-10 kHz cutoff frequency),amplified, and digitized (20 kHz sampling rate) using a Powerlab/8SPwith LabChart v 7.3.2 (ADInstruments, Colorado Springs, Colo., USA),then filtered off-line (40-200 Hz band-pass). Head twitches wereidentified manually based on the following criteria: 1) sinusoidalwavelets; 2) evidence of at least three sequential head movements(usually exhibited as bipolar peaks) with frequency >40 Hz; 3) amplitudeexceeding the level of background noise; 4) duration <0.15 s; and 5)stable coil voltage immediately preceding and following each response.

Data Analysis

Head twitch counts were analysed using one-way analyses of variance(ANOVA). Post hoc pairwise comparisons between selected groups wereperformed using Tukey's studentized range method. Median effective doses(ED50 values) and 95% confidence intervals (95% CI) for HTRdose-response experiments were calculated by nonlinear regression (Prism7.00, GraphPad Software). A gaussian distribution was used to fitbiphasic HTR dose-response data (see FIG. 2A).

The Head Twitch Response Model 2 (Rats)

Animals

A total number of 8 male Sprague Dawley (SD) rats (9-10 weeks old,weighing 300-450 g) were used in a dose response HTR test of compound 8(n=2 animals/dose). The rats were bred and housed at TranslationalNeuropsychiatry Unit (TNU), Aarhus University. They animals were housedin pairs (Cage 1291H Eurostandard Type III H, 425×266×185 mm,Techniplast, Buguggiate, Italy) at 20±2° C. on a 12-h light/dark cycle(lights on at 07:00 am) and had ad libitum access to chow pellets andtap water. The animal colony was protected from outside noise, and allexperimental procedures were performed in specially equipped roomswithin the vivarium. The Danish National Committee for Ethics in AnimalExperimentation had approved all animal procedures prior to initiationof the experiments (2016-15-0201-01105).

Drugs

The doses of compound 8 were established according the use of classicalhallucinogen serotonergic psychedelics drugs in the class ofphenylalkylamines described in the literature¹². Concentrations of0.375, 0.75, 1.5 and 3.0 mg/kg of compound 8 were tested in comparisonwith the administration of saline—NaCl solution—9 mg/mL (VEH) (Freseniuslab, Bad Homburg v.d.H, Germany).

The scale was calibrated and the compound was weighed inside an 1.5 mLeppendorf tube, diluted in NaCl solution—9 mg/mL (Fresenius lab, BadHomburg v.d.H, Germany) and transferred for 15 mL tubes prior to theexperiment day. The drug was stored in −4° C. for the use in thefollowing day. All the doses were calculated and prepared for injectionof a final volume of 1 mL/kg.

Procedure

The animals were randomized and weighed one day prior of the experiment.The cages were transferred from the vivarium to the experiment room 1hour before the experiment start, to acclimate the animals. Beforeinjections, the tubes containing the different doses of the drug werekept at room temperature. The set up was built using 2 cameras to recordeach animal. Camera 1 was located on top of the cage and recorded theanimal from the above, while a frontal camera 2 was recording from theside. 29G sterilized syringes of 0.5 mL (BD Ultra-fine insulin syringe,Beckton Dickinson, Franklin Lakes, N.J., USA) were filled with thevolume calculated according to the individual animal weigh. The drug wasadministered i.p. The animal was transferred to the set up camera roomand placed in a new transparent cage with no lid (482×267×210 mm). Theanimals were observed for 1 hour, while the vehicle group was observedfor 30 min.

After the recording, the animals were placed in their original cageswith water and food ad libitum where they remained for extra 30 min. Atthe endpoint 1.5 h, the animals were euthanized by decapitation. Thebrain structures of frontal cortex, hypothalamus and hippocampus werecollected and frozen on powdered dry ice for further molecular analysis.The tissues were stored at −80° C.

HTR Score

The MTS files from the video-recordings were transferred to the computerand analyzed. The responses producing head shakes were counted andreported in a timeline (see FIG. 2B).

The Flinders Sensitive Line (FSL) Model

Animals Male Flinders line rats (Flinders Sensitive Line (FSL) and theircontrol Flinders Resistant Line (FRL); 9-11 weeks of age; 228-336 g)from the colony maintained at (TNU), Aarhus University (originallyderived from the colony at the University of North Carolina, USA) werehoused in pairs (Cage 1291H Eurostandard Type III H, 425×266×185 mm,Techniplast, Buguggiate, Italy) at 20±2° C. on a 12-h light/dark cycle(lights on at 07:00 am). The animals had ad libitum access to chowpellets and tap water. The animal colony was protected from outsidenoise, and all experimental procedures were performed in speciallyequipped rooms within the vivarium. The Danish National Committee forEthics in Animal Experimentation had approved all animal proceduresprior to initiation of the experiments (2016-15-0201-01105).

Behavioural Tests

Open field test: Compound 8 was dissolved in saline and administeredi.p. at 1.5 mg/kg. The following groups were included in the experiment:FRL-vehicle (n=10), FSL-vehicle (n=10), FSL-ketamine (15 mg/kgS-ketamine, Pfizer) (n=8), and FSL-compound 8 (1.5 mg/kg) (n=10). 50minutes after injection of either vehicle or compound 8, locomotoractivity was assessed in an open field in order to detect possibleinhibitory or stimulatory drug effects that could confound theperformance in the forced swim test (FST). A squared open field arena(plastic; 50×50×37 cm) with a light intensity of approximately 5 lux wasused. Each rat was allowed to move freely for 5 min. The test arena wasthoroughly cleaned with 70% ethanol between each rat to minimize theimpact of olfactory cues. A camera, located directly above the center ofthe field, recorded the session and the total distance moved wasquantified using EthoVision XT video tracking software (version11.0.928; Noldus Information Technology, Wageningen, The Netherlands).

Forced swim test: After the open field test (OFT) and 60 minutes afterinjection of either vehicle or compound 8, the antidepressant potentialwas assessed in a modified FST.¹³ Since FSL rats inherently show adepression-like phenotype, no pre-swim session was required. The rat wasplaced in an acrylic plastic cylinder (60 cm in height, 24 cm indiameter) containing 40 cm of water (25±1° C.) for 7 min. A camera,located directly in front of the cylinder, recorded the session. Anexperienced investigator blinded to the treatments measured the timespent struggling (defined as attempts to climb the cylinder wall ordiving), swimming (defined as a forward propulsion in the watersurface), and being immobile (defined as the absence of movements exceptfor the necessary activities to keep the head above water). Results areshown in FIG. 3.

The Adrenocorticotropic Hormone Model

The adrenocorticotropic hormone model (ACTH) model was conducted aspreviously described¹⁴. Male Sprague Dawley rats were used (age 7 weeks,N=50) (Taconic Biosciences A/S, Lille Skensved, Denmark). After 1 weekhabituation, the rats were given either 100 μg ACTH/animal/day s.c.(Adrenocorticotropic Hormone 1-24 (China Peptides, China)) at 10 a.m.for 14 days (n=30) or vehicle (VEH) consisting of 0.9% saline (n=20). Atday 14, the rats were subjected to a pre-swim test (15 minutes).Following the pre-swim, the rats in the ACTH group (n=30) wereadministered with either 3 injections of imipramine (n=10) (IMI, 15mg/kg (Sigma-Aldrich, Denmark, i.p.), 1 injection of compound 8 (n=10)(1.5 mg/kg i.p.), or vehicle (n=10). The rats in the VEH group (n=20)were administered with either 3 injections of imipramine (n=10) orvehicle (n=10), thus creating 5 groups with 10 animals in each group(VEH-VEH, VEH-IMI, ACTH-VEH, ACTH-IMI, ACTH-compound 8). The 3IMI-injections were given at 24 hours, 18 hours, and 1 hour prior to theforced swim test (FST) at day 15. Compound 8 was given 1 hour prior tothe FST. Preceding the FST, rat baseline mobility was determined in the(OFT). The OFT and the FST were conducted as described above. Resultsare shown in FIGS. 4A and 4B.

Chemical Synthesis General Experimental Details

All reactions were performed under an atmosphere of argon unlessotherwise indicated. Reagents and starting materials were obtained fromcommercial sources and used as received. Solvents were of chromatographygrade or dried either by an SG Water solvent purification system (DCM,DMF, THF) or with 3 molecular sieves (DMSO, toluene, MeCN, Et₂O, EtOH,DME and MeOH). Anhydrous reactions were run in flame- or oven-dried(150° C.) glassware under N₂ or argon. Purification by columnchromatography and dry column vacuum chromatography (DCVC) was donefollowing standard procedures using Merck Kieselgel 60 (40-63 μm or15-40 μm mesh, respectively. Microwave assisted reactions were performedon a Biotage Initiator apparatus in a sealed vial using external surfacesensor for temperature monitoring.

Thin-Laver Chromatography (TLC)

For TLC analysis, pre-coated silica gel 60 F₂₅4 plates purchased fromMerck were used. EtOAc, n-heptane, acetone, toluene, DCM, Et₂O, MeOH,Et₃N, and mixtures thereof were used as eluents. Visualization of thecompounds was achieved with UV light (254 nm), iodine on silica orpotassium permanganate, anisaldehyde, ninhydrin or ferric chloridestains. The denoted retention factors (Rf) were rounded to the nearest0.05.

Liquid Chromatoraraphy Mass Spectrometry (LCMS)

LC/MS analyses were performed on Shimadzu Prominence chromatographconnected to Applied Biosystems API 2000 mass spectrometer, columnPhenomenex Gemini 5 μm C₁₈; 50×2 mm, eluent MeCN (+0.1% HCOOH)/H₂O(+0.1% HCOOH).

High Performance Liquid Chromatography Methods (HPLC)

HPLC retention times (t_(R)) are reported in minutes (min) and weredetermined by different methods, given in parenthesis.

Method A: HPLC was recorded on a Thermo Scientific Dionex 3000 UltiMateinstrument connected to a Thermo Scientific Dionex 3000 Diode ArrayDetector by a Gemini-NX 3 μm C18 110A (250×4.6 mm) column with UVdetection at 205, 210, 254 and 280 nm. Mobile phase (MP) A: 0.1% TFA inH₂O (v/v). MP B: 0.1% TFA, 10% H₂O in MeCN (v/v/v). Flow rate: 1.0mL/min. Gradient: 0-30 min: 0-100% MP B.

Method B: HPLC was recorded on a Thermo Scientific Dionex 3000 UltiMateinstrument connected to a Thermo Scientific Dionex 3000 Diode ArrayDetector using a Gemini-NX 3 μm C18 110A (250×4.6 mm) column with UVdetection at 205, 210, 254 and 280 nm. MP A: 0.1% TFA in H₂O (v/v). MPB: 0.1% TFA, 10% H₂O in MeCN (v/v/v). Flow rate: 1.0 mL/min. Gradient:0-20 min: 0-100% MP B.

Method C (Preparative HPLC): Preparative HPLC was performed on a ThermoScientific Dionex 3000 ultimate instrument connected to a ThermoScientific Dionex 3000 photodiode array detector using a Gemini-NX 5u RPC18 column (250×21.2 mm) with UV detection at 254 and 280 nm. MP A: 0.1%TFA, 100% H₂O (v/v). MP B: 0.1% TFA, 10% H₂O, 90% MeCN (v/v/v). Flowrate 20 mL/min. Gradient: 0-25 min: 0-100% MP B, 25-30 min: 100% MP B.

Method D (Chiral HPLC): Enantiomeric excess (ee) of the desiredenantiomers was determined using a Thermo Scientific Dionex 3000UltiMate instrument connected to a Thermo Scientific Dionex 3000 DiodeArray Detector using an analytical Phenomenex Lux 5 Amylose-2 (250×4.6mm) chiral column with UV detection at 205, 210, 254 and 280 nm. MP A:0.1% Diethylamine in Heptane (v/v). MP B: 0.1% Diethylamine in EtOH(v/v). Flow rate: 10.0 mL/min. using an isocratic gradient: 10% MP B.

High Resolution Mass Spectrometry (HRMS)

Performed by matrix-assisted laser ionisation time-of-flight massspectrometry (MALDI-TOF). Analysis was performed in positive ion modewith MALDI ionization on a Thermo QExactive Orbitrap mass spectrometer(Thermo Scientific, Bremen, Germany) equipped with an AP-SMALDI 10 ionsource (TransmitMIT, Giessen, Germany) and operated with mass resolvingpower 140,000 at m/z 200. 2,5-Dihydroxybenzoic acid was used as matrixand lock-mass for internal mass calibration, providing a mass accuracyof 3 ppm or better. Samples were prepared using 2,5-dihydroxybenzoicacid as the matrix.

Melting Point (MP)

Melting point was measured for recrystallized compounds on a StanfordResearch System OptiMelt capillary melting point apparatus with visualinspection and the values are reported in a range rounded to the nearest0.5° C.

Nuclear Magnetic Resonance Spectroscopy (NMR)

NMR experiments were performed on a 300, 400 or 600 MHz Brukerinstrument or a Varian Mercury (400 MHz) instrument. The obtainedspectra were analysed using MestReNova 11.0 software typically usingWhittaker smoother baseline correction. Chemical shifts are reported inppm (δ) with reference to the deuterated solvent used. Couplingconstants (J) are reported in Hertz (Hz). Multiplet patterns aredesignated the following abbreviations or combinations thereof: br(broad), m (multiplet), s (singlet), d (doublet), t (triplet), q(quartet), p (pentet), sex (sextet) and hep (heptet).

General Procedures

Hydrogenation Procedure A. Hydrogenation of Phenylpyridine Using ParrApparatus

The phenylpyridine (1 eq.) was dissolved in glacial AcOH (1.0 M) in ahydrogenation flask. PtO₂ (0.1 eq.) was added and the reaction vesselwas shaken under H₂ atmosphere (50-60 psi) on a Parr-apparatus for 24 h.Upon completion, the reaction mixture was washed through a pad of Celitewith EtOAc (25 mL) and the filtrate was basified using 35% aq. NaOHsolution. The phases were separated isolated and the aqueous layerfurther extracted with EtOAc (2×50 mL). The combined organic phases weredried over MgSO₄, filtered and evaporated in vacuo.

Hydrogenation Procedure B. Hydrogenation of Phenylpyridines UsingThalesnano H-Cube

The phenylpyridine was dissolved in glacial AcOH (0.01M). ThalesnanoH-Cube was loaded with a fresh catalyst cartridge (Pd(OH)₂/C). Theapparatus was set to run at 100° C. and 80 Barr. The reaction wasfollowed by TLC. Upon complete consumption of starting material, AcOHwas removed in vacuo.

General Procedure C. The Synthesis of Phenylpyrdines

A flame dried round-bottom flask equipped with a stir bar and a cooler,backfilled with N₂ gas was charged with the appropriate boronic acid (1eq.), 3-bromopyridine (1.1 eq.), triphenylphosphine (0.15 eq.) and DME(10 M). 2M aqueous Na₂CO₃ (2.7 eq.) was added followed by Pd/C (0.15mmol). The reaction was stirred at 80° C. for 17 h under N₂ atmosphere.The reaction was allowed to cool to ambient temperature, then filteredover a pad of Celite. The filtrate was diluted with H₂O and EtOAc. Thephases were separated and the aqueous phase further extracted withEtOAc. The combined organic phases were washed with H₂O and brine beforebeing dried over MgSO₄, filtered and evaporated in vacuo. The crudeproduct was purified by flash column chromatography to give the titlecompound.

General Procedure D. The Separation of Enantomeric Mixtures ofFree-Amines

Analytical amounts of the racemate was dissolved in a mixture of MeOH,EtOH and Diethylamine (10:17:0.1) and separated by Enantiomericseparation method 1, 2 or 3 unless otherwise specified. Thehydrochloride salts were prepared by dissolving the products in aminimum amount of Et₂O and treating the solution with 4 M HCl indioxane. The precipitate was isolated by decantation and redissolved inthe minimum amount of MeOH. Et₂O was added dropwise until nucleation wasobserved and the solution was allowed to crystalize at −4° C. overnightgiving the pure title compound as white or off-white solids.Enantiomeric excess (EE) of the desired enantiomer was determined usingChiral HPLC Method 1. (ee>95%). The (S)-enantiomer eluted first. Allother analytical data was identical for both enantiomers.

Enantiomeric Separation Method 1.—Chiral HPLC

Analytical amounts of racemate were dissolved in a mixture of MeOH, EtOHand Diethylamine (10:17) and separated on a Thermo Scientific Dionex3000 UltiMate instrument connected to a Thermo Scientific Dionex 3000Diode Array Detector by a Phenomenex Lux 5 Amylose-2 (250×10 mm) chiralcolumn with UV detection at 205, 210, 254 and 280 nm. MP A: 0.1%Diethylamine in Heptane (v/v). MP B: 0.1% Diethylamine in EtOH (v/v).Flow rate: 10.0 mL/min. using an isocratic gradient of 30-10% MP B.Loadings were between 1-3 mL per injection (3-5 mg/mL). The(S)-enantiomers eluted at retention times between 2 min and 18 mindepending upon loading. Enantiomeric excess (EE) of the desiredenantiomers was determined on an identical instrument using a PhenomenexLux 5 Amylose-2 (250×4.6 mm) chiral column.

Enantiomeric Separation Method 2.—Chiral SFC

Racemic amine as the hydrochloride was dissolved in MeOH and separatedby preparative supercritical fluid chromatography (SFC). Separation wasperformed on a Diacell AD-H chiralpak column (250×21.2 mm) connected toa Berger Multigram II operating at 50 mL/min at 35° C. and 100 barbackpressure using stacked injections. MP: CO₂ (75%) and Ethanol+0.1%diethylamine (25%). UV detection at 290 nM Enantiomeric excess (EE) ofthe enantiomers was determined on a Diacell AD-H chiralpak column 3μ15cm (150×4.6 mm) connected to an Aurora Fusion A5/Agilent SFC systemoperating at 4 mL/min at 40° C. and 150 bar backpressure. MP: CO2 (75%)and Ethanol+0.1% diethylamine (25%).

Enantiomeric Separation Method 3.—Resolution by Chiral Salt Formationand Crystallization

Racemic amine (1 eq.) was dissolved in MeOH (0.5 M) at room temperatureand added over 5 minutes to a boiling solution of L(+)tartaric acid (1eq.) in MeOH (70 mM). Upon complete addition, the reaction was left tocool to room temperature for 48 h yielding white crystalline solidswhich were isolated by filtration. The filtrate was left at 4° C.overnight giving a second crop of solids, isolated by filtration. Cropswere combined and redissolved in boiling MeOH (40 mL) and allowed tocool to room temperature giving white solids which were again subjectedto recrystallization from boiling MeOH (20 mL) eventually giving clearprismatic crystals (5% total yield, 96% enantiomeric excess)

Enantiomeric excess (EE) of the desired enantiomer was determined usinga Thermo Scientific Dionex 3000 UltiMate instrument connected to aThermo Scientific Dionex 3000 Diode Array Detector by a Phenomenex Lux 5Amylose-2 (250×4.6 mm) chiral column with UV detection at 205, 210, 254and 280 nm. MP A: 0.1% Diethylamine in Heptane (v/v). MP B: 0.1%Diethylamine in EtOH (v/v). Flow rate: 10.0 mL/min. using an isocraticgradient of 30-10% MP B.

General Procedure E. The Coupling of Functionalized Sulfonyl Hydrazineswith Boronic Acid to Give Phenyl Azetidines and Phenylpyrrolidine.

A flame dried microwave vial, backfilled with argon gas, was chargedwith sulfonylhydrazone (1 eq.), boronic acid (2 eq.) and dry Cs₂CO₃ (1.1eq.). The contents of the vial were sealed and subjected to high vacuumfor 2 h before re-establishing argon atmosphere. The contents of thevial were suspended in anhydrous 1,4 Dioxane (0.12 M). The suspensionwas thoroughly de-gassed before capping the vial. The reaction washeated to 110° C. under vigorous stirring. After 18 h the reaction wasallowed to cool to ambient temperature and filtered over a plug ofcelite. The filtrate was concentrated in vacuo and immediately subjectedto purification by flash column chromatography (1:2 EtOAc/Heptane)giving the desired compound with minor impurities as a clear oil.

The crude carboxylate was dissolved in 4 M HCl in dioxane (1 mL) andstirred at ambient temperature for 24 h. The pure amine hydrochloridewas precipitated out by the addition of Et₂O (25 mL) and isolated bydecantation giving the title compound.

General Procedure F. Coupling of Pyridyl Boronic Acids with ArylBromides.

A flame dried microwave vial equipped with a stir-bar and backfilledwith argon gas was charged with the corresponding boronic acid (1 eq.)and [1,1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (5mol %) within a glove box and tightly sealed. Aqueous degassed K₃PO₄solution (0.9 M, 1.5 eq.) was added, followed by addition of thecorresponding aryl bromide (1 eq) in degassed dioxane (0.3 M). Theresulting mixture was heated by microwave irradiation at 100° C. for 1h, then allowed to cool to ambient temperature, filtered through asilica pad and further eluted with EtOAc, then evaporated in vacuo. Theresidue was purified by flash-column chromatography using mobile phasemixtures of Petroleum ether/EtOAc.

General Procedure G. Bromination of Phenols.

A flame dried round-bottom flask, equipped with a stir bar and a rubberseptum, backfilled with argon gas, was charged with the correspondingphenol (1 eq.) in DCM and AcOH (2:1, 0.1 M) elemental bromine was added(1.05 eq.) dropwise at 0° C. The reaction mixture was slowly warmed toambient temperature overnight, then evaporated directly in vacuo. Theresidue was purified by flash-column chromatography using mobile phasemixtures of Petroleum ether/EtOAc.

General Procedure H. Methylation of Phenols.

A flame dried microwave vial equipped with a stir bar and backfilledwith argon gas, was charged with the corresponding phenol (1 eq.) inacetone (0.25 M). K₂CO₃, (8 eq.) was added followed by methyl iodide (6eq.). The vial was sealed and the reaction mixture was stirred for 5 hat 60° C. then evaporated directly in vacuo and partitioned between DCMand H₂O. Phases were separated and the aqueous phase further extractedwith DCM. Combined organic extracts were dried over Na₂SO₄, filtered,and evaporated in vacuo. The residue was purified by flash-columnchromatography using mobile phase mixtures of Petroleum ether/EtOAc.

General Procedure J. Ethylation of Phenols.

A flame dried microwave vial equipped with a stir bar and backfilledwith argon gas, was charged with the corresponding phenol (1 eq.) inacetone (0.25M) K₂CO₃, (8 eq) was added followed by bromoethane (5 eq.).The vial was sealed and the reaction mixture was stirred for 5 h at 60°C. then evaporated directly in vacuo and partitioned between DCM andH₂O. Phases were separated and the aqueous phase further extracted withDCM. Combined organic extracts were dried over Na₂SO₄, filtered, andevaporated in vacuo. The residue was purified by flash-columnchromatography using mobile phase mixtures of Petroleum ether/EtOAc.

General Procedure I. Hydrogenation of Pyridines Using Pressure Reactor.

To a stirred solution of the substrate (1 eq.) in glacial AcOH (0.25 M)was added PtO₂ (15 mol %). The reaction mixture was hydrogenated atambient temperature under 10 Bar H₂ pressure in a Buchi tinyclave steelpressure reactor. After 16 h the reaction mixture was filtered through asyringe filter and evaporated in vacuo. The residue was partitionedbetween DCM and aq. sat. NaHCO₃. The organic phase was separated, theaqueous phase was further extracted with DCM. Combined organic extractswere dried over Na₂SO₄, filtered, and evaporated in vacuo. The residuewas used in the next step without further purification.

General Procedure K. Introduction of Boc Protecting Group.

A round-bottom flask was charged with the amine (1 eq.), Boc₂O (1.5 eq.)and Et₃N (2 eq.) was added. The resulting mixture was stirred for 1 h atambient temperature then evaporated to dryness in vacuo. The residue waspurified by flash-column chromatography using mobile phase mixtures ofPetroleum ether/EtOAc.

General Procedure L. Cleavage of Boc Protecting Group.

A round-bottom flask was charged with the carboxylate (1 eq.) andetheral HCl (40 eq.) was added. The solution was stirred for 3-7 days atambient temperature to achieve full conversion eventually giving thedesired product as a white precipitate. The slurry was centrifuged andthe etheral layer discarded. The resulting solids were washed with Et₂Oand evaporated to dryness in vacuo.

General Procedure M. Reductive Amination.

A flame dried round-bottom flask equipped with a stirr bar and a rubberseptum was charged with the amine (1 eq.) and MeOH (61.5 mM). Thecorresponding aldehyde (5 eq.) was added, followed by one drop of AcOH.The resulting mixture was cooled to 0° C., then NaCNBH₃ (3 eq.) wasadded. The reaction mixture was allowed to warm up to room temperatureovernight. DCM was added and the mixture was washed with 1 M NaOH andbrine. The organic phase was dried over anhydrous Na₂SO₄, filtered andevaporated. The residue was taken up in Et₂O and treated with ethereal2M HCl (5 eq.). The resulting suspension was centrifugated. Thesupernatant was discarded, the solid washed with ether, and evaporatedto dryness in vacuo.

General Procedure N. Thioanisole Derivative Synthesis from Bromobenzenes

A flame dried round-bottom flask equipped with a stirr bar and a rubberseptum, backfilled with argon gas, was charged with1,4-Dibromo-2,5-dimethoxybenzene (1 eq.) in dry THE (0.4 M). Theresulting solution was cooled to −78° C. and 2.5 M n-BuLi in Hexanes(1.1 eq.) was added dropwise. The reaction mixture was stirred at thistemperature for for 1 h before the dropwise addition of the appropriatedisulfide (1.1 eq.). The mixture was allowed to warm to ambienttemperature and stirred for 1 h then quenched with 1 M HCl. The mixturewas concentrated under reduced pressure to half of the initial volume.Et₂O was added and phases separated. The organic phase was washed withH₂O and NaHCO₃, then concentrated in vacuo. The residue was purified byflash-column chromatography using mobile phase mixtures of Petroleumether/EtOAc.

General Procedure. Thioanisole Derivative Synthesis from Fluorobenzenes

A flame dried round-bottom flask equipped with a stirr bar and a cooler,backfilled with argon gas, was charged with3-(5-fluoro-2-methoxy-4-(trifluoromethyl)phenyl)pyridine (1 eq) andanhydrous DMF (233 M). To this suspension was added the appropriatesodium thiolate (1.5 eq). The resulting mixture was heated to 50° C. for24 h. After cooling to ambient temperature, the reaction mixture wasconcentrated in vacuo and the resulting crude residue was partitionedbetween Et₂O and H₂O. The organic phase was isolated and the aqueousphase further extracted with Et₂O. Combined organic extracts were driedover anhydrous Na₂SO₄, filtered, and evaporated in vacuo. The residuewas purified by flash-column chromatography using mobile phase mixturesof Petroleum ether/EtOAc.

Synthesis of Compound 1 and 2

4-methoxybenzenesulfonohydrazide

A round bottom flask equipped with a stir bar and a rubber septum wascharged with 4-methoxybenzenesulfonyl chloride (5.17 g, 25 mmol) in THE(125 mL) and cooled to 0° C. 50% aq. hydrazine solution (3.90 mL, 62.5mmol) was added via dropwise addition. The reaction mixture was stirredat 0° C. for 1 h before being evaporated in vacuo. The crude residue waspartitioned between H₂O (50 mL) and EtOAc (100 mL) and phases wereseparated. The aqueous phase was further extracted with EtOAc (2×100mL). Combined organic phases were washed with H₂O water (50 mL) andbrine (50 mL), dried over Na₂SO₄, filtered and evaporated in vacuo toyield the title compound as a colorless amorphous solid (3.79 g, 75%).¹H-NMR (600 MHz, CDCl₃) δ 7.85 (d, J=8.9 Hz, 2H), 7.02 (d, J=8.9 Hz,2H), 5.55 (s, 1H), 3.89 (s, 3H), 3.59 (s, 2H); ¹³C-NMR (151 MHz, CDCl₃)δ 163.86, 130.63, 127.64, 114.68, 55.86.

tert-butyl3-(2-((4-methoxyphenyl)sulfonyl)hydrazineylidene)azetidine-1-carboxylate

To a flame dried microwave vial, backfilled with argon gas, was added4-methoxybenzenesulfonohydrazide (3.83 g, 18.91 mmol) and tert-butyl3-oxoazetidine-1-carboxylate (3.24 g, 18.93 mmol). The contents of thevial were dissolved in anhydrous DMSO (13 mL). The vial was capped andheated to 60° C. The reaction was followed by H-NMR. Upon completion,the reaction mixture was poured into H₂O (350 mL) and the aqueousmixture extracted with Et₂O (3×100 mL). Combined organic phases werewashed with H₂O (5×50 mL) and brine (50 mL), dried over Na₂SO₄, filteredand evaporated in vacuo to give the crude compound, in quantitativeyields, as an off-white solid with minor impurities. The product wasdeemed of sufficient purity for use in the subsequent reactions withoutfurther purification. TLC Rf=0.1 (33% EtOAc in Heptane v/v); ¹H-NMR (400MHz, DMSO-d₆) δ 7.70 (dd, J=8.9, 3.4 Hz, 3H), 7.08 (dd, J=8.8, 4.2 Hz,3H), 4.48-4.34 (m, 3H), 3.80 (d, J=3.1 Hz, 4H), 1.33 (bs, 9H); ¹³C-NMR(101 MHz, DMSO-d₆) δ 163.13, 156.17, 148.44, 130.86, 130.00, 114.85,79.96, 56.16, 28.38.

(4-bromo-2,5-dimethoxyphenyl)boronic acid

To a flame dried vessel, backfilled with argon gas, was added1,4-dibromo-2,5-dimethoxybenzene (2.22 g, 7.5 mmol) and anhydrous THE(75 mL). the reaction was cooled to −78° C. before the slow, dropwiseaddition of n-BuLi solution (2.17 M, 7.5 mmol). The solution was stirredat −78° C. for 20 minutes before the addition of Triisopropyl borate(5.19 mL, 22.5 mmol). The cooling source was removed and the reactionwas allowed to reach ambient temperature and stirred on for anadditional 20 h before quenching by careful addition of 2 M aq. HClsolution (15 mL). The aqueous mixture was diluted with Et₂O (100 mL) andphases were separated. The aqueous phase was further extracted with Et₂O(2×100 mL). Combined organic phases were washed with H₂O (50 mL), driedover Na₂SO₄, filtered through a plug of silica and evaporated to givethe title compound as a crude white solid with minor impurities. Theproduct was deemed of sufficient purity for use in the subsequentreactions without further purification.

(2,5-dimethoxy-4-(trifluoromethyl)phenyl)boronic acid

A flame dried vessel, backfilled with argon gas, was charged with1-bromo-2,5-dimethoxy-4-(trifluoromethyl)benzene (1.00 g, 3.52 mmol) andanhydrous THE (75 mL) and cooled (−78° C.) before the slow, dropwiseaddition of n-BuLi (2.3 M, 7.04 mmol). The solution was stirred at −78°C. for 20 minutes before the addition of triisopropyl borate (5.19 mL,22.5 mmol). The cooling source was removed and the reaction was allowedto reach ambient temperature and stirred on for an additional 20 hbefore quenching the reaction by careful addition of 0.5 M aq. HClsolution (25 mL) followed by H₂O (50 mL). The reaction was concentratedin vacuo and the remaining aqueous mixture was diluted with DCM (50 mL)and phases were separated. The aqueous phase was further extracted withDCM (2×50 mL). Combined organic phases were washed with H₂O (50 mL),dried over MgSO₄, filtered through a silica plug and evaporated to givethe crude compound as an off-white solid in quantitative yields withminor impurities. The product was deemed of sufficient quality for usein the subsequent reactions without further purification.

3-(4-bromo-2,5-dimethoxyphenyl)azetidine hydrochloride (1)

Synthesized according to general procedure E using tert-butyl3-(2-((4-methoxyphenyl)sulfonyl)hydrazineylidene)azetidine-1-carboxylate(249 mg, 0.70 mmol), (4-bromo-2,5-dimethoxyphenyl)boronic acid (365 mg,1.40 mmol). The title compound was isolated as a colorless crystallinesolid (26 mg, 12%). TLC Rf=0.1 (33% EtOAc in Heptane v/v); ¹H-NMR (600MHz, MeOD) δ 7.22 (s, 1H), 6.91 (s, 1H), 4.35 (d, J=3.3 Hz, 2H), 4.33(s, 2H), 4.30-4.25 (m, 1H), 3.85 (s, 6H); ¹³C-NMR (151 MHz, MeOD) δ153.17, 151.74, 127.91, 117.33, 113.85, 112.06, 57.57, 56.69, 52.50,34.73; HRMS m/z calculated for [C₁₁H₁₅BrNO₂]⁺ (M_(freebase)+H) 272.0281;found: 272.0282.

3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)azetidine hydrochloride (2)

Synthesized according to general procedure E using tert-butyl3-(2-((4-methoxyphenyl)sulfonyl)hydrazineylidene)azetidine-1-carboxylate(257 mg, 0.72 mmol), (2,5-dimethoxy-4-(trifluoromethyl)phenyl)boronicacid (362 mg, 1.45 mmol). The title compound was isolated as a colorlesscrystalline solid (15.3 mg, 7%). ¹H-NMR (600 MHz, MeOD) δ 7.19 (s, 1H),7.04 (s, 1H), 4.39-4.34 (m, 5H), 3.89 (s, 6H); ¹³C-NMR (151 MHz, MeOD) δ151.61, 150.72, 131.66, 124.36, 112.79, 109.08, 109.04, 55.81, 55.20,51.00, 33.38; HRMS m/z calculated for [C₁₂H₁₅F₃NO₂]⁺ (M_(free base)+H)262.1049; found: 262.1051.

Synthesis of Compound 3 and 4

tert-butyl(E)-3-(((4-methoxyphenyl)sulfonyl)diazenyl)pyrrolidine-1-carboxylate

A flame dried microwave vial, backfilled with argon gas, was chargedwith 4-methoxybenzenesulfonohydrazide (1.6 g, 7.9 mmol) and tert-butyl3-oxopyrrolidine-1-carboxylate (1.46 g, 7.9 mmol) and anhydrous MeOH (35mL). The vial was capped and heated to 60° C. for 18 h. The reaction wasfollowed by ¹H-NMR. Upon completion, the reaction mixture was pouredinto H₂O (350 mL) and extracted with Et₂O (3×100 mL). Combined organicphases were washed with H₂O (5×50 mL) and brine (50 mL), dried overNa₂SO₄, filtered and evaporated in vacuo to give the crude compound, inquantitative yields, as an off-white solid with minor impurities. Theproduct was deemed of sufficient quality for use in the subsequentreactions without further purification. ¹H-NMR (400 MHz, CDCl₃) δ 7.88(d, J=8.9 Hz, 2H), 7.04-6.92 (m, 2H), 3.99 (bs, 1H), 3.92 (bs, 1H), 3.87(bs, 3H), 3.80 (bs, 1H), 3.75 (bs, 1H), 2.68 (m, 2H), 2.54 (s, 1H), 1.44(s, 10H); ¹³C-NMR (101 MHz, CDCl₃) δ 26.3 (br), 28.4, 30.6 (br), 43.9(br), 46.5 (br), 49.5 (br), 55.6, 80.1, 80.4, 114.3, 129.6, 131.3,154.1, 159.9, 163.5.

tert-butyl 3-(2,5-dimethoxyphenyl)pyrrolidine-1-carboxylate

Synthesized according to general procedure E tert-butyl(E)-3-(((4-methoxyphenyl) sulfinyl)diazenyl)pyrrolidine-1-carboxylate(369.4 mg, 1 mmol), (2,5-dimethoxyphenyl)boronic acid (363.9 mg, 2mmol). The title compound was isolated as a brown oil (42.6 mg, 13%).TLC Rf 0.3 (20% EtOAc in Heptane v/v); ¹H-NMR (400 MHz, CDCl₃) δ6.83-6.66 (m, 3H), 3.79 (s, 4H), 3.76 (s, 4H), 3.64 (tt, J=9.7, 6.9 Hz,1H), 3.56 (ddd, J=11.2, 8.1, 3.3 Hz, 1H), 3.38 (ddd, J=10.7, 9.0, 6.9Hz, 1H), 3.25 (dd, J=10.5, 8.6 Hz, 1H), 2.17 (dtd, J=12.8, 6.6, 3.3 Hz,1H), 2.05-1.92 (m, 1H), 1.47 (s, 9H). ¹³C-NMR (151 MHz, CDCl₃) δ 154.74,153.79, 151.88, 131.10, 113.78, 111.45, 111.40, 79.19, 56.08, 51.13,45.66, 37.71, 31.34, 28.71.

3-(2,5-dimethoxyphenyl)pyrrolidine hydrochloride

To a round bottom flask, equipped with a stir bar, charged withtert-butyl 3-(2,5-dimethoxyphenyl)pyrrolidine-1-carboxylate (72 mg, 0.23mmol) and MeOH (2 mL), was added 4 M HCl in dioxane (0.5 mL). Thereaction was stirred at ambient temperature for 2 h giving precipitationof the hydrochloride. The precipitate was isolated by decantation anddissolved in the minimum amount of MeOH. Et₂O was added dropwise untilnucleation was observed and the solution was allowed to crystalize at−4° C. overnight giving the pure title compound as a white solid (54 mg,94%). ¹H-NMR (600 MHz, MeOD) δ 6.97 (dd, J=8.4, 0.9 Hz, 1H), 6.88-6.85(m, 2H), 3.86 (s, 3H), 3.78 (s, 3H), 3.77-3.70 (m, 1H), 3.72-3.66 (m,1H), 3.58 (ddd, J=11.8, 8.4, 3.6 Hz, 1H), 3.38 (ddd, J=11.6, 9.7, 7.2Hz, 1H), 3.26 (dd, J=11.0, 9.3 Hz, 1H), 2.40 (dh, J=14.1, 3.6, 3.2 Hz,1H), 2.22 (dtd, J=13.0, 9.7, 8.4 Hz, 1H); ¹³C-NMR (151 MHz, MeOD)155.30, 152.98, 129.00, 115.59, 113.43, 112.93, 56.30, 56.15, 50.73,46.84, 40.06, 30.92; HPLC t_(R)=9.88 (Method B).

(R)-3-(4-bromo-2,5-dimethoxyphenyl)pyrrolidine (3) hydrobromide and(5)-3-(4-bromo-2,5-dimethoxyphenyl)pyrrolidine hydrobromide (4)

A flame dried vessel, backfilled with argon gas, was charged with3-(2,5-dimethoxyphenyl)pyrrolidine hydrochloride (63.3 mg, 0.26 mmol),and glacial AcOH (1 mL). A solution of elemental bromine (14 μL, 0.28mmol) in glacial AcOH (1 mL) was added dropwise. The reaction wasshielded from light and stirred at ambient temperature. The reaction wasmonitored by TLC. Upon completion, the reaction was diluted with H₂O (5mL) and washed with Et₂O (10 mL). The aqueous mixture was basified with10% aq. NaOH solution and extracted with EtOAc (15 mL) followed by amixture of EtOH and Chloroform (1:2) (2×15 mL). The combined organicswere dried over MgSO4, filtered and evaporated in vacuo giving the crudehydrobromide as a brown solid in high purity (59 mg, 62%). Analyticalamounts of the racemic mixture was separated and isolated as the twoindividual enantiomers as their hydrochloride salts using generalprocedure D using an isocratic gradient of 25% MP B. Enantiomer 1(compound 4): Rt 18.03, Enantiomer 2 (compound 3): Rt 2=26.02; ¹H-NMR(600 MHz, DMSO-d6) δ 8.88 (s, 2H), 7.25 (s, 1H), 7.06 (s, 1H), 3.84 (s,3H), 3.80 (s, 3H), 3.64 (tt, J=9.7, 7.8 Hz, 1H), 3.53 (dd, J=11.3, 8.2Hz, 1H), 3.41 (ddd, J=11.9, 8.4, 3.8 Hz, 1H), 3.25 (ddd, J=11.5, 9.3,7.2 Hz, 1H), 3.13 (dd, J=11.3, 9.7 Hz, 1H), 2.26 (dtd, J=12.5, 7.3, 3.8Hz, 1H), 2.08-1.99 (dtd, 1H).); ¹³C-NMR (151 MHz, DMSO-d6) δ 151.42,149.60, 127.90, 116.11, 112.57, 109.15, 56.88, 56.39, 48.85, 44.88,36.98, 29.92; HPLC t_(R)=18.30 (Method A); HRMS m/z calculated for[C₁₂H₁₆BrNO₂]⁺ (M_(freebase)+H) 286.0437, found 286.0439.

Synthesis of Compound 5 and 6

(R)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)pyrrolidine (5) and(S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)pyrrolidine (6)

A flame dried microwave vial, backfilled with argon gas, was chargedwith tert-butyl(E)-3-(((4-methoxyphenyl)sulfonyl)diazenyl)pyrrolidine-1-carboxylate(841 mg, 2.27 mmol), (2,5-dimethoxy-4-(trifluoromethyl)phenyl)boronicacid (860 mg, 3.45 mmol) and dry Cs₂CO₃ (1.12 g, 3.45 mmol). Thecontents of the vial were sealed and subjected to high vacuum for 1 hbefore reestablishing argon atmosphere. The contents of the vial weresuspended in anhydrous 1,4 Dioxane (0.12 M). The suspension wasthoroughly degassed before capping the vial. The reaction was heated to150° C. by microwave irradiation under vigorous stirring. After 1 h, thereaction was allowed to cool to ambient temperature and filtered over aplug of Celite and washed through with EtOAc (20 mL). The filtrate waswashed with H₂O (20 mL) and brine (20 mL), dried over MgSO₄, evaporatedin vacuo and subjected to purification by flash column chromatography(1:2 EtOAc/Heptane), removing major impurities giving the boc-protectedamine with minor impurities as a brown oil. The crude product wasfurther purified by Prep HPLC (HPLC Method C) giving the pure racemicmixture as white solids (69.9 mg, 6%). Analytical amounts of the racemicmixture were separated and the two individual enantiomers isolated astheir hydrochloride salts using general procedure D using a isocraticgradient of 15% MP B. Enantiomer 1 (compound 6): Rt 6.16, Enantiomer 2(compound 5): Rt 7.36. Both compounds were re-purified by preparativeHPLC (HPLC Method C) finally isolating the title compounds as theirtrifluoroacetate salts in analytical amounts. ¹H-NMR (600 MHz, MeOD) δ7.20 (s, 1H), 7.12 (s, 1H), 3.91 (s, 3H), 3.91 (s, 3H), 3.82 (tt, J=9.1Hz, 1H), 3.72 (dd, J=11.4, 8.4 Hz, 1H), 3.61 (ddd, J=11.8, 8.4, 3.6 Hz,1H), 3.44-3.37 (ddd, 1H), 3.36-3.35 (m, 1H), 2.45 (dtd, J=14.0, 7.3, 3.5Hz, 1H), 2.27 (dtd, J=12.9, 9.8, 8.3 Hz, 1H); ¹³C-NMR (151 MHz, MeOD) δ151.63, 150.83, 132.34, 126.20 (q), 117.95 (q), 112.99, 109.30 (q),55.77, 55.20, 48.96, 45.47, 38.80, 29.44; HPLC t_(R)=19.87 (Method A);HRMS m/z calculated for [C₁₃H₁₇F₃NO₂]⁺ (M_(free base)+H) 276.1206, found276.1206.

Synthesis of Compound 7 and 8

1,4-Dimethoxy-2-(trifluoromethyl)benzene

To a flame dried round-bottom flask, backfilled with argon gas,containing a solution a solution of sodium methoxide (40.52 g, 750 mmol)in anhydrous degassed DMSO (150 mL) was added1-fluoro-4-methoxy-2-(trifluromethyl)benzene (14.56 g, 75 mmol). Thereaction was stirred at 120° C. for 19 h until full consumption ofstarting material was observed by NMR. The reaction was quenched withice H₂O (700 mL) and organics were extracted with Et₂O (3×200 mL). Thecombined organic phases were washed with H₂O (2×200 mL), followed bybrine (200 mL), then dried over MgSO₄, filtered and concentrated invacuo to give the desired dimethoxy benzene as a clear oil. The oilcrystalized into a solid over the course of several days and was ofsufficiently high purity to use without further purification (15.21 g,98%). TLC Rf=0.45 (20% EtOAc in Heptane v/v); 1H-NMR (400 MHz, CDCl₃) δ7.12 (d, J=3.1 Hz, 1H), 7.02 (dd, J=9.0, 3.1 Hz, 1H), 6.94 (d, J=9.0 Hz,1H), 3.86 (s, 3H), 3.80 (s, 3H).); ¹³C-NMR (151 MHz, CDCl₃) δ 153.12,151.70, 126.27, 124.47, 122.66, 120.85, 119.90, 119.69, 119.49, 119.28,118.27, 113.77, 113.00, 112.96, 56.75, 56.06; HPLC tR=26.79 min (MethodA)

1-Bromo-2,5-dimethoxy-4-(trifluoromethyl)benzene

A flame dried round-bottom flask, backfilled with argon gas, was chargedwith 1,4-dimethoxy-2-(trifluoromethyl)benzene (5.15 g, 25 mmol) andanhydrous DCM (50 mL). The reaction was shielded from light and cooledon an ice-bath before addition of TfOH (4.43 mL, 50 mmol). The reactionmixture was stirred for 2 minutes followed by the addition of1,3-Dibromo-5,5-dimethylhydantoin (3.57 g, 12.5 mmol) in one portion.The reaction mixture was stirred on for additional 5 minutes beforebeing allowed to warm to ambient temperature and stirred on for a totalof 3 h. The reaction was then quenched by careful addition of sat. aq.Na₂S₂O₃ (7 mL) followed by sat. aq. NaHCO₃ (30 mL). The resultingbiphasic system was separated and the aqueous phase further extractedwith DCM (2×50 mL). The combined organic phases were washed with brine(50 mL), dried over Na₂SO₄, then filtered and concentrated in vacuo togive a crude off-white solid that was dissolved in boiling isopropanoland allowed to cool to ambient temperature. Et₂O was added dropwiseuntil turbidity was observed then the reaction was allowed to stand at4° C. overnight giving the desired bromide (4.63 g, 65%) as a colorlesscrystalline solid. TLC Rf=0.6 (10% EtOAc in Heptane v/v)¹H-NMR (400 MHz,CDCl₃) δ 7.23 (s, 1H), 7.09 (s, 1H), 3.87 (d, J=10.6 Hz, 6H); ¹³C-NMR(151 MHz, CDCl₃)) δ 151.77, 149.86, 123.21 (q, J_(CF)=270.9 Hz), 118.51(q, J_(CF)=31.3), 118.23, 116.37, 110.86 (q, C_(F)=3.6 Hz), 57.16,56.95. HPLC tR=28.64 min (Method A)

3-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)pyridine

To a flame dried 20 mL microwave vial, backfilled with argon gas, wasadded 1-Bromo-2,5-dimethoxy-4-(trifluoromethyl)benzene (909 mg, 3.1mmol) followed by pyridin-3-ylboronic acid (762 mg, 6.2 mmol) andanhydrous, degassed 1, 4 dioxane (3.5 mL). The mixture was furtherdegassed for 10 minutes before addition ofBis(triphenylphosphine)palladium(II) dichloride (109 mg, 0.155 mmol, 5mol %) followed by 1M solution of tri-tert-butylphosphine in toluene(0.155 mL, 0.155 mmol). Finally, a degassed 2M aq. solution of Na₂CO₃(3.1 mL, 6.2 mmol) was added before sealing the reaction vial. Thereaction was heated to 120° C. using microwave irradiation for 80minutes. The reaction was monitored by TLC. Upon complete consumption ofthe bromide. The reaction mixture was diluted with EtOAc (7 mL) andtransferred to a separation funnel containing EtOAc (10 mL) and H₂O (20mL). Phases were separated and the aqueous phase further extracted withEtOAc (10 mL). The combined organic phases were washed with brine (20mL), dried over MgSO₄, filtered and concentrated in vacuo to mixed wetsolids. The crude product was immediately purified by flash columnchromatography (2:5, EtOAc in Heptane). Giving the desired phenylpyridine as an off-white solid. TLC Rf=0.18 (40% EtOAc in Heptane v/v);¹H-NMR (400 MHz, CDCl₃)) δ 8.75 (d, J=2.1 Hz, 1H), 8.60 (dd, J=4.9, 1.7Hz, 1H), 7.86 (dt, J=7.9, 2.0 Hz, 1H), 7.40-7.31 (m, 1H), 7.19 (s, 1H),6.97 (s, 1H), 3.90 (s, 3H), 3.80 (s, 3H); ¹³C-NMR (151 MHz, CDCl₃) δ151.76, 150.14, 150.05, 148.88, 136.88, 133.22, 131.63, 123.49 (q,J_(CF)=273.6 Hz), 123.13, 118.99 (q, J_(CF)=31.3 Hz), 115.28, 110.76 (q,J_(CF)=5.4 Hz), 56.85, 56.49; HPLC tR=20.23 (Method A)

(R)-3-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)piperidine hydrochloride(7) and (S)-3-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)piperidinehydrochloride (8)

Synthesized according to Hydrogenation procedure A or B using3-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)pyridine (4 g, 14.12 mmol).The hydrochloride salt was prepared by dissolving the product in aminimum amount of Et₂O and treating the solution with 4 M dioxanal HCl.The precipitate was isolated by decantation and redissolved in theminimum amount of MeOH. Et₂O was added dropwise until nucleation wasobserved and the solution was allowed to crystalize at −4° C. overnightgiving the pure title compound as a white solid (2.82 g, 69%). Theracemic mixture was separated and isolated as the two individualenantiomers as their hydrochloride salts using general procedure D usingan isocratic gradient of 10% MP B. Enantiomer 1 (compound 8): Rt 7.22,Enantiomer 2 (compound 7): Rt 11.247. Chiral resolution was alsoachieved using enantiomeric separation method 2 and 3. MP 239-241° C.;TLC Rf=0.3 (5% TEA and 10% MeOH in EtOAc v/v/v); ¹H-NMR (400 MHz,CDCl₃)) δ 7.19 (s, 1H), 7.12 (s, 1H), 3.92 (s, 3H), 3.90 (s, 3H),3.59-3.42 (m, 3H), 3.20 (t, J=12.3 Hz, 1H), 3.15-3.04 (m, 1H), 2.16-2.07(m, 1H), 2.05-1.88 (m, 3H); ¹³C-NMR (151 MHz, CDCl3)) δ 153.18, 151.73,135.59, 124.92 (q, J=271.6 Hz), 118.81 (q, J=31.3 Hz), 113.75, 110.62(q, J=5.4 Hz), 57.22, 56.73, 45.19, 35.41, 28.84, 23.98; HPLCt_(R)=11.75 (Method A); HRMS m/z calculated for [C₁₄H₁₉F3NO₂]⁺(M_(free base)+H) 290.1362, found 290.1377.

Synthesis of Compounds 9 and 10

3-(2,5-Dimethoxyphenyl)pyridine

Synthesized according to general procedure C. using (2,5-Dimethoxyphenyl)boronic acid (2.184 g, 2.3 mmol). The crude productwas purified by flash column chromatography (40% EtOAc in Heptane v/v)to give the title compound in quantative yield as a clear oil with minorimpurities. The product was deemed of sufficient purity and was used insubsequent reactions without further purification. TLC Rf=0.3 (40% EtOAcin Heptane v/v); ¹H-NMR (400 MHz, CDCl₃) δ 8.77 (d, J=1.8 Hz, 1H), 8.54(dd, J=4.7, 1.6 Hz, 1H), 7.84 (dt, J=7.9, 1.9 Hz, 1H), 7.30 (ddd, J=7.9,4.8, 0.9 Hz, 1H), 6.92-6.85 (m, 3H), 3.78 (s, 3H), 3.73 (s, 3H).);¹³C-NMR (101 MHz, CDCl₃) δ 153.89, 150.83, 150.16, 148.03, 136.77,134.10, 127.91, 122.90, 116.56, 113.92, 112.66, 56.19, 55.79; HPLCt_(R)=9.88 (Method B).

3-(2,5-Dimethoxyphenyl)piperidine

Synthesized according to general procedure B using3-(2,5-Dimethoxyphenyl)pyridine (6.012 g, 27.93 mmol). The hydrochloridesalt was prepared by dissolving the product in a minimum amount of Et₂Oand treating the solution with 4 M HCl in dioxane. The precipitate wasisolated by decantation and redissolved in the minimum amount of MeOH.Et₂O was added dropwise until nucleation was observed and the solutionwas allowed to crystalize at −4° C. overnight giving the pure titlecompound as large white crystals (3.44 g, 48%). TLC Rf=0.2 (5% TEA and10% MeOH in EtOAc v/v/v); ¹H-NMR (400 MHz, CDCl₃) δ 9.84 (s, 1H), 9.44(s, 1H), 6.80-6.63 (m, 3H), 3.75 (s, 3H), 3.74 (s, 3H), 3.59-3.39 (m,3H), 3.06 (q, J=11.4 Hz, 1H), 2.85 (q, J=12.1, 11.6 Hz, 1H), 2.24-2.05(m, 1H), 1.96 (q, J=13.4, 12.3 Hz, 3H), 1.83-1.65 (m, 1H); ¹³C-NMR (101MHz, CDCl₃) δ 153.66, 151.38, 129.72, 114.23, 112.32, 111.65, 55.78,55.75, 47.57, 44.08, 35.35, 28.28, 22.85; HPLC t_(R)=17.04 (Method A).

(R)-3-(4-Chloro-2,5-dimethoxyphenyl)piperidine (9) and(S)-3-(4-Chloro-2,5-dimethoxyphenyl)piperidine (1

To a flame dried round-bottom flask, backfilled with argon gas, wascharged with 3-(2,5-dimethoxyphenyl)piperidine (500 mg, 1.93 mmol),N-Chlorosuccinimide (310 mg, 2.32 mmol) and MeCN. The solution wascooled (0° C.), TiCl₄ (0.2 mL, 1.93 mmol) was slowly added and thereaction was stirred for 10 min. The cooling source was removed and thereaction was stirred on for an additional 5 min before being quenchedwith MeOH (8 mL). The reaction was allowed to warm to ambienttemperature then basified (pH 9) with aq. NaOH solution (10% v/v) underprecipitation of white solid. The solution was clarified by filtrationover a fritted glass funnel and washed through with EtOAc (50 mL). Thefiltrate was washed with sat. aq. Na₂CO₃ (50 mL) and brine (50 mL),dried over MgSO₄, filtered and concentrated in vacuo to give the crudefree-base with minimal impurities as a yellow solid (529 mg, 94% crudeyield). Analytical amounts of the racemic mixture was separated andisolated as the two individual enantiomers as their hydrochloride saltswith minor impurities using general Procedure D using an isocraticgradient of 30% MP B. Enantiomer 1 (compound 10): Rt 6.943, Enantiomer 2(compound 9): Rt 13.493. Both enantiomers were recrystallized again frommixture of EtOAc, Isopropanol and Et₂O giving both enantiomers in highpurity. MP 235-236° C.; TLC Rf=0.2 (5% TEA and 10% MeOH in EtOAc v/v/v);¹H-NMR (400 MHz, CDCl₃) δ 7.07 (s, 1H), 6.99 (s, 1H), 3.88 (s, 3H), 3.85(s, 3H), 3.49-3.38 (m, 3H), 3.15-3.09 (m, 1H), 3.06 (td, J=12.8, 3.5 Hz,1H), 2.15-2.04 (m, 1H), 2.01-1.86 (m, 3H); ¹³C-NMR (101 MHz, CDCl3) δ152.55, 150.87, 129.61, 122.80, 114.52, 113.63, 57.50, 56.74, 49.05,45.18, 35.17, 28.95, 24.05; HPLC tR=18.54 (Method A); HRMS m/zcalculated for [C13H18ClNO2]⁺ (M_(free base)+H) 256.1099, found256.1102.

Synthesis of Compounds 11 and 12

(R)-3-(4-bromo-2,5-dimethoxyphenyl)piperidine (11) and(S)-3-(4-bromo-2,5-dimethoxyphenyl)piperidine (12)

A round-bottom flask, equipped with a stir bar, was charged with3-(2,5-dimethoxyphenyl)piperidine (1 g, 3.87 mmol) and glacial AcOH (19mL). A solution of elemental bromine (0.19 mL, 3.87 mmol) in glacialAcOH (10 mL) was added dropwise. The mixture was stirred for 30 minuntil complete precipitation of product as a white solid. The reactionwas diluted with Et₂O (20 mL) and solids were isolated by filtration.Product was recrystallized from a mixture of boiling MeOH, Isopropanoland Et₂O to give the product as a white solid (853.5 mg, 58%).Analytical amounts of the racemic mixture were separated and isolated asthe two individual enantiomers as their hydrochloride salts usinggeneral procedure D using an isocratic gradient of 25% MP B. Enantiomer1 (compound 12): Rt 7.200, Enantiomer 2 (compound 11): Rt 12.160. MP253-254° C.; TLC Rf=0.15 (0.01% TEA and 25% MeOH in EtOAc v/v/v); ¹H-NMR(400 MHz, MeOD) δ 7.22 (s, 1H), 6.97 (s, 1H), 3.87 (d, J=9.6 Hz, 6H),3.45 (t, J=12.9 Hz, 3H), 3.22-2.99 (m, 2H), 2.11 (d, J=10.7 Hz, 1H),2.04-1.84 (m, 3H); ¹³C-NMR (101 MHz, MeOD) δ 152.76, 151.94, 130.33,117.44, 113.33, 111.54, 57.61, 56.79, 45.23, 35.27, 28.90, 24.06. HPLCtR=14.07 (Method A); HRMS m/z calculated for [C13H18BrNO2]⁺(M_(free base)+H) 300.0594, found 300.0588.

Synthesis of Compounds 13 and 14

(R)-3-(4-Iodo-2,5-dimethoxyphenyl)piperidine (13) and(S)-3-(4-Iodo-2,5-dimethoxyphenyl)piperidine (14)

A flame dried round-bottom flask, equipped with a stir bar, backfilledwith argon gas, was charged with 3-(2,5-Dimethoxyphenyl)piperidine) (500mg, 1.9 mmol), TEA (0.53 mL, 3.8 mmol) and DCM. The reaction mixture wascooled to 0° C. over an ice bath and trifluoroacetic anhydride (483.06mg, 2.3 mmol) was carefully added under vigorous stirring. The reactionwas stirred for 5 minutes at 0° C. before being allowed to warm toambient temperature and stirred for 40 min. The reaction was monitoredby TLC. Upon completion the reaction was quenched with H₂O (20 mL) andphases were separated. The aqueous layer was further extracted withEtOAc (2×50 mL). The combined organic layers were washed with H₂O (50mL) and brine (50 mL) then dried over MgSO₄, filtered and concentratedin vacuo to give the crude triflouroacetamide in quantative yield. TLCRf=0.5 (33% EtOAc in Heptane v/v). The crude product was dissolved inMeOH (20 mL) and purged with a flow of argon gas. The reaction wascooled to 0° C. over an ice bath and shielded from light with aluminiumfoil. AgNO₃ (355 mg, 2.09 mmol) was added in one portion followed by I2(578 mg, 2.28 mmol) in several small portions. The reaction was stirredat 0° C. for 1.75 h, then washed over a plug of celite into a mixture ofice and sat. aq. NaHSO₃. The mixture was allowed to warm to ambienttemperature and organics were evaporated in vacuo. The remaining aqueousmixture was extracted with EtOAc (3×50 mL). The combined organic phaseswere washed with H₂O (50 mL) and brine (50 mL), dried over MgSO₄,filtered and concentrated in vacuo, giving the crude iodide as a yellowoil. Major impurities were removed by flash column chromatography (33%EtOAc in Heptane v/v). The protected iodide was suspended in MeOH (15mL) and 25% aq. NaOH solution (2 ml) was added. The reaction was gentlywarmed with a heat gun until complete solution and left to stir untilTLC showed complete deprotection of the amine. The reaction wasconcentrated in vacuo and partitioned between a mixture of EtOAc, DCMand H₂O (1:1:2, v/v). The aqueous phase was further extracted with DCM(2×50 mL). The combined organic phases were washed with H₂O (50 mL) andbrine (50 mL), dried over MgSO₄, filtered and concentrated in vacuo togive the pure iodide (471 mg, 71%) as clear oil. Analytical amounts ofthe racemic mixture was separated and isolated as the two individualenantiomers as their hydrochloride salts using general procedure D usingusing an isocratic gradient of 30% MP B. Enantiomer 1 (compound 14): Rt6.95, Enantiomer 2 (compound 13): Rt 10.163. MP 252-255° C.; TLC Rf=0.15(5% TEA and 10% MeOH in EtOAc v/v/v)¹H-NMR (400 MHz, CDCl₃) δ 7.38 (s,1H), 6.87 (s, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.48-3.38 (m, 3H), 3.12(t, J=13.0 Hz, 1H), 3.06 (td, J=11.2, 9.9, 2.2 Hz, 1H), 2.14-2.06 (m,1H), 2.02-1.87 (m, 3H); ¹³C-NMR (101 MHz, CDCl3) δ 154.58, 152.99,131.38, 123.26, 111.92, 84.88, 57.66, 56.78, 48.94, 45.18, 35.40, 28.85,24.03; HPLC tR=18.96 (Method A); HRMS m/z calculated for [C₁₃H₁₈INO₂]⁺(M_(free base)+H) 348.0455 found 348.0453.

Synthesis of Compounds 15 and 16

tert-Butyl 3-(2,5-dimethoxyphenyl)piperidine-1-carboxylate

A flame dried round-bottom flask, equipped with a stir bar, backfilledwith argon gas, was charged with 3-(2,5-dimethoxyphenyl)piperidine (1 g,3.87 mmol) and di-tert-butyl dicarbonate (931.39 mg, 4.26 mmol). Thecontents of the vessel were suspended in a mixture of TEA in DCM (1:10v/v) (12 mL). The reaction was stirred at room temperature for 18 h. Thereaction was monitored by TLC. Upon complete conversion to thecarboxylate, the reaction was concentrated in vacuo. Major impuritieswere removed by flash column chromatography (20% EtOAc in Heptane v/v)to give the protected amine as a clear oil in quantitative yield. Theproduct was deemed of sufficient purity for use in subsequent reactionsand was not further purified. TLC Rf=0.35 (20% EtOAc in Heptane v/v);¹H-NMR (400 MHz, CDCl₃) δ 6.80 (d, J=8.7 Hz, 1H), 6.75 (d, J=3.0 Hz,1H), 6.71 (dd, J=8.7, 3.0 Hz, 1H), 4.17 (s, 2H), 3.80 (s, 3H), 3.77 (s,3H), 3.11-2.96 (m, 1H), 2.70 (dd, J=12.8, 11.2 Hz, 2H), 1.94 (d, J=8.2Hz, 1H), 1.80-1.68 (m, 1H), 1.67-1.53 (m, 2H), 1.46 (s, 9H); ¹³C-NMR(101 MHz, CDCl₃) δ 155.00, 153.79, 151.60, 133.33, 114.11, 111.58,110.98, 79.34, 56.19, 55.85, 36.07, 32.04, 28.66, 25.75, 22.84, 14.26;HPLC tR=17.04 (Method A).

tert-Butyl 3-(4-formyl-2,5-dimethoxyphenyl)piperidine-1-carboxylate

A flame dried round-bottom flask, equipped with a stir bar, backfilledwith argon gas, was charged with tert-Butyl3-(2,5-dimethoxyphenyl)piperidine-1-carboxylate (1.03 g, 3.2 mmol) andanhyd. DCM (7 mL). The reaction was cooled (−78° C.) and TiCl₄ (0.87 mL,8.0 mmol) was added followed by Dichloromethyl methyl ether (1103.50 g,9.6 mmol) and monitored by TLC. Upon completion the reaction was allowedto warm to 0° C. under stirring, then poured into ice (50 mL). Ice wasallowed to melt before the mixture was basified with sat. aq. NaHCO₃(100 mL) and drops of concentrated NaOH and phases were separated. Theaqueous layer was further extracted with a mixture of EtOH and CHCl₃(1:2 v/v)(3×150 mL). The combined organic layers were dried over MgSO₄,filtered and concentrated in vacuo to give the crude product as a yellowsolid. To ensure full protection of the amine, the crude product wassuspended in a mixture of TEA in DCM (1:10 v/v) (10 mL) anddi-tert-butyl dicarbonate (769 mg, 3.5 mmol) was added. The mixture wasleft to stir for 16 h. The reaction mixture was concentrated in vacuoand purified by repeated flash column chromatography (25% EtOAc inHeptane). Two purifications gave the pure title compound as a clear oil(786 mg, 70%). TLC Rf=0.3 (25% EtOAc in Heptane v/v)(Development:Ninhydrine); ¹H-NMR (400 MHz, CDCl₃) δ 10.40 (s, 1H), 7.29 (s, 1H), 6.82(s, 1H), 4.26-4.01 (m, 2H), 3.89 (s, 3H), 3.83 (s, 3H), 3.12 (tt,J=10.8, 3.7 Hz, 1H), 2.81 (s, 2H), 2.01-1.90 (m, 1H), 1.75 (d, J=10.6Hz, 1H), 1.67-1.56 (m, 2H), 1.46 (s, 9H); ¹³C-NMR (101 MHz, CDCl₃) δ189.12, 156.77, 154.78, 151.40, 141.08, 123.14, 108.41, 79.46, 56.24,55.85, 36.67, 31.87, 29.00, 28.47, 25.25, 22.68, 14.10.

tert-Butyl 3-(4-cyano-2,5-dimethoxyphenyl)piperidine-1-carboxylate

A flame dried round-bottom flask, equipped with a stir bar, backfilledwith argon gas, was charged with of tert-Butyl3-(4-formyl-2,5-dimethoxyphenyl)piperidine-1-carboxylate (786 mg, 2.24mmol), NaN₃ (219 mg, 3.38 mmol) and MeCN (5 mL).Trifluoromethanesulfonic acid (0.59 mL, 6.75 mmol) was added dropwiseover approximately 1 min. The reaction was stirred at room temperaturefor 3 min before being concentrated in vacuo and diluted with H₂O (2mL). The aqueous mixture was basified with sat. aq. NaHCO₃ (5 mL) anddrops of NaOH (z pH 10). The basic aqueous suspension was extracted witha mixture of EtOH in CHCl3 (1:2)(3×50 mL). The combined organic phaseswere dried over MgSO₄, filtered and concentrated in vacuo to a browngum. To ensure full protection of the amine the crude product wassuspended in a mixture of TEA in DCM (11 mL, 1:10 v/v) and di-tert-butyldicarbonate (540 mg, 2.47 mmol) was added. The mixture was left to stirfor 16 h. The reaction mixture was concentrated in vacuo and purified byflash column chromatography (25% EtOAc in Heptane) to give the purenitrile as a white solid (298 mg, 38%). TLC Rf=0.3 (25% EtOAc in Heptanev/v)(Development: Ninhydrine); ¹H-NMR (400 MHz, CDCl3) δ 6.97 (s, 1H),6.79 (s, 1H), 4.30-3.96 (m, 2H), 3.89 (s, 3H), 3.81 (s, 3H), 3.09 (ddt,J=10.7, 7.3, 3.7 Hz, 1H), 2.80 (s, 2H), 1.98-1.88 (m, 1H), 1.74 (s, 1H),1.69-1.54 (m, 3H), 1.46 (s, 10H); ¹³C-NMR (101 MHz, CDCl₃) δ 156.08,154.89, 151.07, 139.55, 116.77, 114.55, 111.13, 99.27, 79.67, 56.62,56.20, 36.61, 28.61, 27.56, 25.33

(R)-2,5-dimethoxy-4-(piperidin-3-yl)benzonitrile (15) and(S)-2,5-dimethoxy-4-(piperidin-3-yl)benzonitrile (16)

A round-bottom flask, equipped with a stir bar, was charged withtert-Butyl 3-(4-cyano-2,5-dimethoxyphenyl)piperidine-1-carboxylate (150mg. 0.44 mmol) and MeOH (5 mL). 4 M Dioxanal HCl was gradually addedover 2 h (1.7 mL, 6.8 mmol). The reaction was monitored by TLC. Uponfull conversion additional Et₂O was added until nucleation was observedand reaction was left to crystalize at −4° C. overnight yielding thepure nitrile as the hydrochloride salt as off green crystals, which wereisolated by decantation then stripped of remaining solvent traces invacuo and further dried under reduced pressure (78 mg, 62%). Analyticalamounts of the racemic mixture was separated and isolated as the twoindividual enantiomers as their hydrochloride salts in quantitativeyields using general procedure D using an isocratic gradient of 30% MPB. Enantiomer 1 (compound 16): Rt 8.527, Enantiomer 2 (compound 15): Rt11.860. MP 252-254° C. TLC Rf=0.1 (25% EtOAc in Heptanev/v)(Development: Ninhydrine)¹H-NMR (400 MHz, CDCl₃) δ 7.27 (s, 1H),7.10 (s, 1H), 3.97 (s, 3H), 3.90 (s, 3H), 3.61-3.41 (m, 3H), 3.19 (t,J=12.3 Hz, 1H), 3.15-3.03 (m, 1H), 2.13 (dd, J=10.0, 3.4 Hz, 1H), 1.98(tdd, J=16.3, 15.0, 6.7, 3.4 Hz, 3H); ¹³C-NMR (101 MHz, CDCl₃) δ 156.13,150.75, 136.30, 115.68, 114.75, 111.26, 99.60, 55.83, 55.42, 43.77,34.24, 27.30, 22.52; HPLC tR=9.75 (Method B);). IR vmax (neat)/cm−12225,11(CN); HRMS m/z calculated for [C18H14N2O2]⁺ (Mfree base+H)247.1441, found 247.1446.

Synthesis of Compounds 17 and 18

(4-bromo-2,5-dimethoxyphenyl)(methyl)sulfane

The title compound was prepared according to the general Procedure Nstarting from 1,4-dibromo-2,5-dimethoxybenzene (500 mg, 1.689 mmol). 860mg (49%) of the title compound were prepared. ¹H-NMR (300 MHz, CDCl₃) δ7.01 (s, 1H), 6.78 (s, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 2.44 (s, 3H).

3-(2,5-dimethoxy-4-(methylthio)phenyl)pyridine

The title compound was prepared according to the general procedure Fstarting from (4-bromo-2,5-dimethoxyphenyl)(methyl)sulfane (568 mg,2.158 mmol). 351 mg (62%) of the title compound were prepared. ¹H-NMR(400 MHz, CDCl3) δ: 8.76 (dd, J=2.3, 0.9 Hz, 1H); 8.55 (dd, J=4.8, 1.7Hz, 1H); 7.85 (ddd, J=7.9, 2.3, 1.7 Hz, 1H); 7.32 (ddd, J=7.9, 4.8, 0.9Hz, 1H); 6.86 (s, 1H); 6.80 (s, 1H); 3.90 (s, 3H); 3.79 (s, 3H); 2.50(s, 3H). MS: m/z 262 [M+H]⁺.

(R)-3-(2,5-dimethoxy-4-(methylthio)phenyl)piperidine hydrochloride (17)and (S)-3-(2,5-dimethoxy-4-(methylthio)phenyl)piperidine hydrochloride(18)

The title compounds were prepared according to the general procedure Istarting from 3-(2,5-dimethoxy-4-(methylthio)phenyl)pyridine (350 mg,1.339 mmol). The material obtained after filtration of the catalyst andevaporation. The compound was purified by flash-column chromatographywith MeOH/EtOAc (+5% Et₃N) mobile phase. The enantiomers were separatedon Daicel Chiralpak IG 250×30 mm, 5 μm; mobile phase: 30%Isopropanol/70% Heptane (+0.1% diethylamine); elution: isocratic;detection: UV 210 nm; flow rate: 40 mL/min. Analytical column: ChiralpakIG 250×4.6 mm, 5 μm; mobile phase: 30% Isopropanol/70% Heptane (+0.1%diethylamine); elution: isocratic; detection: UV 210 nm; flow rate: 1mL/min. Enantiomer 1: Rt 16.70 min (35 mg, 10%). Enantiomer 2: Rt 21.75min (35 mg, 10%). Both enantiomers were further converted to thecorresponding hydrochlorides using general procedure L in quantitativeyields. ¹H-NMR (400 MHz, MeOD) δ: 6.83 (s, 1H), 6.81 (s, 1H), 3.85 (s,3H), 3.82 (s, 3H), 3.45-3.34 (m, 3H), 3.10-2.98 (m, 2H), 2.41 (s, 3H),2.10-2.03 (m, 1H), 1.97-1.84 (m, 3H). ¹³C-NMR (100 MHz, MeOD) δ 152.9,152.3, 128.5, 127.1, 111.6, 111.2, 57.2, 56.7, 49.3, 45.2, 35.1, 29.1,24.1, 14.8. MS: m/z 268 [M+H]⁺

Synthesis of Compounds 19 and 20

2-bromo-4-ethoxy-5-(trifluoromethyl)phenol

The title compound was prepared according to the general procedure G.starting from commercially available 4-ethoxy-3-(trifluoromethyl)phenol(2.00 g, 9.701 mmol). 2.60 g (94%) of the title compound were prepared.¹H-NMR (400 MHz, CDCl₃) δ 7.23 (s, 1H), 7.10 (s, 1H), 4.04 (q, J=7.2 Hz,2H), 1.42 (t, J=7.2 Hz, 3H).

1-bromo-5-ethoxy-2-methoxy-4-(trifluoromethyl)benzene

The title compound was prepared according to the general procedure Hstarting from 2-bromo-4-ethoxy-5-(trifluoromethyl)phenol (1.14 g, 4.013mmol). 1.07 g (89%) of the title compound were prepared. ¹H-NMR (400MHz, CDCl₃) δ: 7.22 (s, 1H), 7.08 (s, 1H), 4.07 (q, J=6.8 Hz, 2H), 3.88(s, 3H), 1.42 (t, J=6.8 Hz, 3H).

3-(5-ethoxy-2-methoxy-4-(trifluoromethyl)phenyl)pyridine

The title compound was prepared according to the general procedure Fstarting from 1-bromo-5-ethoxy-2-methoxy-4-(trifluoromethyl)benzene(1.00 mg, 3.343 mmol). 801 mg (81%) of the title compound were prepared.¹H-NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.61 (s, 1H), 7.87 (dt, J=8.0,1.8 Hz, 1H), 7.38 (dd, J=7.9, 4.8 Hz, 1H), 7.18 (s, 1H), 6.97 (s, 1H),4.12 (q, J=7.0 Hz, 2H), 3.80 (s, 3H), 1.44 (t, J=7.0 Hz, 3H). MS: m/z298 [M+H]⁺.

(R)-3-(5-ethoxy-2-methoxy-4-(trifluoromethyl)phenyl)piperidinehydrochloride (19) and(S)-3-(5-ethoxy-2-methoxy-4-(trifluoromethyl)phenyl)piperidinehydrochloride (20)

The title compounds were prepared according to the general procedure Lstarting from from3-(5-ethoxy-2-methoxy-4-(trifluoromethyl)phenyl)pyridine. Theenantiomers were transformed to the corresponding ter-butyl carboxylatesusing general procedure K and separated using a Daicel Chiralpak IG250×30 mm, 5 μm; mobile phase: 5% Isopropanol/95% Heptane; elution:isocratic; detection: UV 210 nm; flow rate: 40 mL/min. Enantiomer 1(compound 19): Rt 15.35 min (95 mg, 74%), Enantiomer 2 (compound 20): Rt26.79 min (90 mg, 77%). The carboxylates were liberated as thecorresponding hydrochlorides using general procedure L. giving thetitles compounds in quantative yields. The hydrochorides were furtheranalyzed using a Thermo Scientific Dionex 3000 UltiMate instrumentconnected to a Thermo Scientific Dionex 3000 Diode Array Detector by aPhenomenex Lux 5 Amylose-2 (250×4.6 mm) chiral column with UV detectionat 205, 210, 254 and 280 nm. MP A: 0.1% Diethylamine in Heptane (v/v).MP B: 0.1% Diethylamine in EtOH (v/v). Flow rate: 10.0 mL/min. using anisocratic gradient of 10% MP B to ensure correct stereochemistry.Enatiomer 1 (compound 20): Rt 5.300, Enantiomer 2 (compound 19): Rt5.970. ¹H-NMR (400 MHz, MeOD) δ: 7.15 (s, 1H); 7.05 (s, 1H); 4.12 (q,2H, J=7.0 Hz); 3.86 (s, 3H); 3.52-3.36 (m, 3H); 3.17-2.98 (m, 2H);2.13-2.03 (m, 1H); 2.02-1.84 (m, 3H); 1.39 (t, 3H, J=7.0 Hz). ¹³C-NMR(100 MHz, MeOD; one signal overlapping with CD₃OD) δ: 152.6, 151.7,135.5, 124.9 (q, J=271.6 Hz), 119.3 (q, J=31.0 Hz), 114.8, 110.4 (q,J=5.5 Hz), 66.5, 56.7, 45.2, 35.3, 28.8, 24.0, 15.1. MS: m/z 304 [M+H]⁺.

Synthesis of Compounds 21 and 22

1-bromo-2,5-diethoxy-4-(trifluoromethyl)benzene

The title compound was prepared according to the general procedure Jstarting from 2-bromo-4-ethoxy-5-(trifluoromethyl)phenol (1.14 mg, 4.013mmol). 1.18 mg (94%) of the title compound were prepared. ¹H NMR (400MHz, CDCl₃) δ: 7.20 (s, 1H), 7.08 (s, 1H), 4.07 (qd, J=7.0, 2.7 Hz, 4H)1.44 (dt, J=14.8, 7.0 Hz, 6H).

3-(2,5-diethoxy-4-(trifluoromethyl)phenyl)pyridine

The title compound was prepared according to the general procedure Estarting from 1-bromo-2,5-diethoxy-4-(trifluoromethyl)benzene (1.12 mg,3.577 mmol). 768 mg (69%) of the title compound were prepared. ¹H-NMR(400 MHz, CDCl3) a: 8.78 (s, 1H), 8.60 (s, 1H), 7.90 (dt, J=7.9, 1.9 Hz,1H), 7.38 (dd, J=7.9, 4.9 Hz, 1H), 7.18 (s, 1H), 6.97 (m, 1H), 4.12 (q,J=7.0 Hz, 2H), 4.01 (q, J=7.0 Hz, 2H), 1.43 (t, J=7.0 Hz, 3H), 1.32 (t,J=6.9 Hz, 3H). MS: m/z 312 [M+H]⁺

(R)-3-(2,5-diethoxy-4-(trifluoromethyl)phenyl)piperidine hydrochloride(21) and (S)-3-(2,5-diethoxy-4-(trifluoromethyl)phenyl)piperidinehydrochloride (22)

The title compounds were prepared according to the general procedure Lstarting from from 3-(2,5-diethoxy-4-(trifluoromethyl)phenyl)pyridine.The enantiomers were transformed to the corresponding ter-butylcarboxylates using general procedure K and separated using a DaicelChiralpak IG 250×30 mm, 5 μm; mobile phase: 5% Isopropanol/95% Heptane;elution: isocratic; detection: UV 210 nm; flow rate: 40 mL/min.Enantiomer 1 (compound 21): Rt 7.03 min (45 mg, 34%), Enantiomer 2(compound 22): Rt 8.69 min (30 mg, 34%). The carboxylates were liberatedas the corresponding hydrochlorides using general procedure L giving thetitles compounds in quantative yields. The hydrochorides were furtheranalyzed using a Thermo Scientific Dionex 3000 UltiMate instrumentconnected to a Thermo Scientific Dionex 3000 Diode Array Detector by aPhenomenex Lux 5 Amylose-2 (250×4.6 mm) chiral column with UV detectionat 205, 210, 254 and 280 nm. MP A: 0.1% Diethylamine in Heptane (v/v).MP B: 0.1% Diethylamine in EtOH (v/v). Flow rate: 10.0 mL/min. using anisocratic gradient of 10% MP B to ensure correct stereochemistry.Enatiomer 1 (compound 22): Rt 5.850, Enantiomer 2 (compound 21): Rt6.490. ¹H-NMR (400 MHz, MeOD) δ: 7.13 (s, 1H); 7.05 (s, 1H); 4.17-4.03(m, 4H); 3.54-3.38 (m, 3H); 3.19-2.98 (m, 2H); 2.15-2.03 (m, 1H);2.02-1.85 (m, 3H); 1.44 (t, 3H, J=7.0 Hz); 1.39 (t, 3H, J=7.0 Hz).¹³C-NMR (100 MHz, MeOD; one signal overlapping with CD₃OD) δ: 152.5,151.0, 135.6, 125.0 (q, J=271.6 Hz), 119.3 (q, J=31.0 Hz), 114.8, 111.5(q, J=5.4 Hz), 66.5, 65.9, 45.2, 35.4, 28.9, 24.0, 15.2, 15.1. MS: m/z318 [M+H]⁺.

Synthesis of Compounds 23 and 24

3-(2,5-dimethoxy-4-methylphenyl)pyridine

The title compound was prepared according to the general procedure Estarting from 1-bromo-2,5-dimethoxy-4-methylbenzene (277 mg, 1.20 mmol).263 mg (95%) of the title compound were prepared.

¹H-NMR (300 MHz, CDCl3) S: 8.77 (s, 1H); 8.54 (d, J=4.8 Hz, 1H); 7.87(dt, J=7.9, 1.9 Hz, 1H); 7.33 (dd, J=7.9, 4.8 Hz, 1H); 6.84 (s, 1H);6.80 (s, 1H); 3.83 (s, 3H); 3.76 (s, 3H), 2.28 (s, 3H). MS: m/z 230[M+H]⁺

(R)-3-(2,5-dimethoxy-4-methylphenyl)piperidine hydrochloride (23) and(S)-3-(2,5-dimethoxy-4-methylphenyl)piperidine hydrochloride (24)

The title compounds were prepared according to the general procedure Istarting from 3-(2,5-dimethoxy-4-methylphenyl)pyridine. The enantiomerswere transformed to the corresponding ter-butyl carboxylates usinggeneral procedure K and separated using a Daicel Chiralpak IG 250×30 mm,5 μm; mobile phase: 5% Isopropanol/95% Heptane; elution: isocratic;detection: UV 210 nm; flow rate: 40 mL/min. Enantiomer 1 (compound 24):Rt 9.38 min (50 mg, 39%), Enantiomer 2 (compound 23): Rt 12.84 min (40mg, 45%). The carboxylates were liberated as the correspondinghydrochlorides using general procedure L giving the titles compounds inquantitative yields. ¹H-NMR (400 MHz, CD₃OD) 6.81 (s, 1H); 6.76 (s, 1H);3.80 (s, 3H); 3.79 (s, 3H); 3.45-3.33 (m, 3H); 3.10-2.97 (m, 2H); 2.17(s, 3H); 2.10-2.02 (m, 1H); 1.98-1.84 (m, 3H). ¹³C-NMR (100 MHz, CD₃OD,one signal overlapping with CD₃OD) δ: 153.4, 152.0, 127.6, 127.5, 115.2,110.9, 56.6, 56.5, 45.2, 35.3, 29.1, 24.1, 16.2. MS: m/z 336 [M+H]⁺

Synthesis of Compounds 25 and 26

(4-bromo-2,5-dimethoxyphenyl)(isopropyl)sulfane

The title compound was prepared according to the general procedure Nstarting from 1,4-dibromo-2,5-dimethoxybenzene (1.50 mg, 5.068 mmol).794 mg (54%) of the title compound were prepared. MS: m/z 232 [M+H]⁺

3-(4-(isopropylthio)-2,5-dimethoxyphenyl)pyridine

The title compound was prepared according to the general procedure Fstarting from (4-bromo-2,5-dimethoxyphenyl)(isopropyl)sulfane (789 mg,2.709 mmol) 589 mg (75%) of the title compound were prepared. MS: m/z290 [M+H]⁺

(R)-3-(4-(isopropylthio)-2,5-dimethoxyphenyl)piperidine (25) and(S)-3-(4-(isopropylthio)-2,5-dimethoxyphenyl)piperidine (26)

The title compounds were prepared according to the general procedure Istarting from 3-(4-(isopropylthio)-2,5-dimethoxyphenyl)pyridine (590 mg,2.039 mmol). The material obtained after filtration of the catalyst andevaporation was purified by flash-column chromatography with MeOH/EtOAc(+5% Et₃N) mobile phase. The enantiomers were separated on DaicelChiralpak IG 250×30 mm, 5 μm; mobile phase: 15% Isopropanol/85% Heptane(+0.1% diethylamine); elution: isocratic; detection: UV 210 nm; flowrate: 40 mL/min. Analytical column: Chiralpak IG 250×4.6 mm, 5 μm;mobile phase: 15% Isopropanol/85% Heptane (+0.1% diethylamine); elution:isocratic; detection: UV 210 nm; flow rate: 1 mL/min. Enantiomer 1(compound 26): Rt 13.01 min (41 mg, 7%). Enantiomer 2 (compound 25): Rt18.13 min (40 mg, 7%). Both enantiomers were further converted to thecorresponding hydrochlorides using general procedure L giving the titlecompounds in quantitative yields. ¹H-NMR (400 MHz, MeOD) δ 6.97 (s, 1H),6.85 (s, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.49 (p, J=6.6 Hz, 1H),3.44-3.31 (m, 3H), 3.12-2.96 (m, 2H), 2.10-2.01 (m, 1H), 1.99-1.82 (m,3H), 1.22 (s, 3H), 1.21 (s, 3H). ¹³C-NMR (100 MHz, MeOD, one signaloverlapping with CD₃OD) δ 154.6, 152.2, 129.8, 124.6, 117.2, 112.3,57.2, 56.6, 45.2, 37.4, 35.2, 29.0, 24.1, 23.3. MS: m/z 296 [M+H]⁺.

Synthesis of Compounds 27 and 28

(4-bromo-2,5-dimethoxyphenyl)(ethyl)sulfane

The title compound was prepared according to the general procedure Nstarting from 1,4-dibromo-2,5-dimethoxybenzene (1.50 mg, 5.068 mmol).610 mg (43%) of the title compound were prepared.

3-(4-(ethylthio)-2,5-dimethoxyphenyl)pyridine

The title compound was prepared according to the general procedure Fstarting from (4-bromo-2,5-dimethoxyphenyl)(ethyl)sulfane (589 mg, 2.125mmol). 407 mg (69%) of the title compound were prepared. MS: m/z 276[M+H]⁺

(R)-3-(2,5-dimethoxy-4-(ethylthio)phenyl)piperidine hydrochloride (27)and (S)-3-(2,5-dimethoxy-4-(ethylthio)phenyl)piperidine hydrochloride(28)

The title compounds were prepared according to the general procedure Istarting from 3-(2,5-dimethoxy-4-(ethylthio)phenyl)pyridine (407 mg,1.478 mmol). The material obtained after filtration of the catalyst andevaporation was purified by flash-column chromatography with MeOH/EtOAc(+5% Et₃N) mobile phase. The enantiomers were separated on DaicelChiralpak IG 250×30 mm, 5 μm; mobile phase: 15% Isopropanol/85% Heptane(+0.1% diethylamine); elution: isocratic; detection: UV 210 nm; flowrate: 40 mL/min. Analytical column: Chiralpak IG 250×4.6 mm, 5 μm;mobile phase: 150% Isopropanol/85% Heptane (+0.1% diethylamine);elution: isocratic; detection: UV 210 nm; flow rate: 1 mL/min. Theenantiomer with a Enantiomer 1 (compound 28): Rt 14.92 min (45 mg, 11%).Enantiomer 2 (compound 27): Rt 19.30 (59 mg, 14%). Both enantiomers werefurther converted to the corresponding hydrochlorides using generalprocedure L in quantitative yields. ¹H-NMR (400 MHz, MeOD) δ 6.91 (s,1H), 6.83 (s, 1H), 3.83 (s, 3H), 3.83 (s, 3H), 3.45-3.33 (m, 3H),3.12-2.97 (m, 2H), 2.91 (q, J=7.4 Hz, 2H), 2.11-2.02 (m, 1H), 1.99-1.82(m, 3H), 1.26 (t, J=7.4 Hz, 3H). ¹³C-NMR (100 MHz, MeOD, one signaloverlapping with CD₃OD) δ 153.4, 152.5, 128.4, 125.9, 114.1, 112.1,57.1, 56.7, 45.2, 35.2, 29.0, 27.0, 24.1, 14.69. MS: m/z 282 [M+H]⁺

Synthesis of Compounds 29 and 30

1-bromo-2-ethoxy-5-methoxy-4-(trifluoromethyl)benzene

The title compound was prepared according to the general procedure Jstarting from 2-bromo-4-methoxy-5-(trifluoromethyl)phenol (700 mg, 2.583mmol). 767 mg (99%) of the title compound were prepared. ¹H-NMR (400MHz, CDCl₃) δ: 7.21 (s, 1H), 7.09 (s, 1H), 4.05 (q, J=6.0 Hz), 1.46 (t,J=6.0 Hz).

3-(2-ethoxy-5-methoxy-4-(trifluoromethyl)phenyl)pyridine

The title compound was prepared according to the general procedure Fstarting from 1-bromo-2-ethoxy-5-methoxy-4-(trifluoromethyl)benzene (755mg, 2.52 mmol). 540 mg (72%) of the title compound were prepared. ¹H-NMR(300 MHz, CDCl3) δ: 8.78 (dd, J=2.3, 0.9 Hz, 1H), 8.60 (dd, J=4.8, 1.7Hz, 1H), 7.89 (ddd, J=7.9, 2.3, 1.7 Hz, 1H), 7.36 (ddd, J=7.9, 4.9, 0.9Hz, 1H), 7.19 (s, 1H), 6.98 (s, 1H), 4.01 (q, J=7.0 Hz, 2H), 3.90 (s,3H), 1.32 (t, J=7.0 Hz, 3H). MS: m/z 298 [M+H]⁺.

(R)-3-(2-ethoxy-5-methoxy-4-(trifluoromethyl)phenyl)piperidinehydrochloride (29) and(S)-3-(2-ethoxy-5-methoxy-4-(trifluoromethyl)phenyl)piperidinehydrochloride (30)

The title compounds were prepared according to the general procedure Lstarting from 3-(2-ethoxy-5-methoxy-4-(trifluoromethyl)phenyl)pyridine.The enantiomers were transformed to the corresponding ter-butylcarboxylates using general procedure K and separated using DaicelChiralpak IG 250×30 mm, 5 μm; mobile phase: 2% Isopropanol/98% Heptane;elution: isocratic; detection: UV 210 nm; flow rate: 40 mL/min.Enantiomer 1 (compound 29): Rt 8.65 min (85 mg, 32%), Enantiomer 2(compound 30): Rt 9.43 min (91 mg, 32%). The carboxylates were liberatedas the corresponding hydrochlorides using general procedure L giving thetitles compounds in quantitative yields. The hydrochorides were furtheranalyzed using a Thermo Scientific Dionex 3000 UltiMate instrumentconnected to a Thermo Scientific Dionex 3000 Diode Array Detector by aPhenomenex Lux 5 Amylose-2 (250×4.6 mm) chiral column with UV detectionat 205, 210, 254 and 280 nm. MP A: 0.1% Diethylamine in Heptane (v/v).MP B: 0.1% Diethylamine in EtOH (v/v). Flow rate: 10.0 mL/min. using anisocratic gradient of 10% MP B to ensure correct stereochemistry.Enatiomer 1 (compound 30): Rt 5.600, Enantiomer 2 (compound 29): Rt6.31. ¹H-NMR (400 MHz, MeOD) δ 7.14 (s, 1H), 7.07 (s, 1H), 4.08 (q,J=7.0 Hz, 2H), 3.88 (s, 3H), 3.55-3.39 (m, 3H), 3.17 (t, J=12.3 Hz, 1H),3.11-2.98 (m, 1H), 2.14-2.03 (m, 1H), 2.02-1.86 (m, 3H), 1.44 (t, J=7.0Hz, 3H). ¹³C-NMR (100 MHz, MeOD; one signal overlapping with CD₃OD) δ153.1, 151.0, 135.8, 124.9 (q, J=271.5 Hz), 118.8 (q, J=31.0 Hz), 113.6,111.7 (q, J=5.4 Hz), 65.9, 57.2, 45.2, 35.4, 28.9, 24.0, 15.2. MS: m/z304 [M+H]⁺.

Synthesis of Compounds 31 and 32

2-bromo-5-ethyl-4-methoxyphenol

The title compound was prepared according to the general procedure Gstarting from known 3-ethyl-4-methoxyphenol (2.083 g, 13.687 mmol).1.810 g (57%) of the title compound were prepared. ¹H-NMR (300 MHz,CDCl₃) δ: 6.88 (s, 1H), 6.84 (s, 1H), 3.76 (s, 3H), 2.55 (q, J=6.1 Hz,2H), 1.16 (t, J=6.1 Hz, 1H).

1-bromo-4-ethyl-2,5-dimethoxybenzene

The title compound was prepared according to the general procedure Hstarting from 2-bromo-5-ethyl-4-methoxyphenol (1.46 g, 6.318 mmol). 400g (26%) of the title compound were prepared. ¹H-NMR (300 MHz, CDCl₃) δ:7.04 (s, 1H), 6.78 (s, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 2.62 (q, J=6.1Hz, 2H), 1.21 (t, J=6.1 Hz, 3H).

3-(4-ethyl-2,5-dimethoxhenyl)pyridine

The title compound was prepared according to the general procedure Fstarting from 1-bromo-4-ethyl-2,5-dimethoxybenzene (400 mg, 1.632 mmol).163 mg (41%) of the title compound were prepared. ¹H-NMR (300 MHz,CDCl₃) δ: 8.78 (s, 1H); 8.55 (s, 1H); 7.87 (d, J=8.0 Hz, 1H); 7.39-7.28(m, 1H); 6.85 (s, 1H); 6.82 (s, 1H); 3.83 (s, 3H); 3.77 (s, 3H); 2.69(q, J=7.5 Hz, 2H); 1.24 (t, J=7.5 Hz, 3H). MS: m/z 244 [M+H]⁺

(R)-3-(4-ethyl-2,5-dimethoxyphenyl)piperidine hydrochloride (31) and(S)-3-(4-ethyl-2,5-dimethoxyphenyl)piperidine hydrochloride (32)

The title compounds was prepared according to the general procedure Lstarting from 3-(4-ethyl-2,5-dimethoxyphenyl)pyridine. The enantiomerswere transformed to the corresponding ter-butyl carboxylates usinggeneral procedure K and separated using a Daicel Chiralpak IG 250×30 mm,5 μm; mobile phase: 2% Isopropanol/98% Heptane; elution: isocratic;detection: UV 210 nm; flow rate: 40 mL/min. Enantiomer 1 (compound 32):Rt 11.35 min (32 mg, 49% mg), Enantiomer 2 (compound 31): Rt 14.10 min(32 mg, 49%). The carboxylates were liberated as the correspondinghydrochlorides using general procedure L giving the titles compounds inquantative yields. ¹H-NMR (400 MHz, MeOD) δ 6.80 (s, 1H), 6.78 (s, 1H),3.81 (s, 3H), 3.79 (s, 3H), 3.46-3.33 (m, 3H), 3.12-2.97 (m, 2H), 2.60(q, J=7.5 Hz, 2H), 2.11-2.01 (m, 1H), 1.98-1.83 (m, 3H), 1.15 (t, J=7.5Hz, 3H). ¹³C-NMR (100 MHz, MeOD; one signal overlapping with CD₃OD) δ153.0, 152.2, 133.7, 127.7, 113.8, 111.3, 56.6, 56.5, 45.2, 35.3, 29.1,24.4, 24.1, 14.9. MS: m/z 250 [M+H]⁺

Synthesis of Compounds 33 and 34

2-bromo-4-ethoxy-5-ethylphenol

The title compound was prepared according to the general procedure Gstarting from known 3-ethyl-4-ethoxyphenol (1.96 g, 11.792 mmol). 930 mg(32%) of the title compound were prepared. ¹H-NMR (300 MHz, CDCl₃) δ:6.88 (s, 1H), 6.84 (s, 1H), 3.94 (q, J=6.4 Hz, 2H), 2.57 (q, J=6.3 Hz,2H), 1.39 (t, J=6.4 Hz, 3H), 1.16 (t, J=6.3 Hz, 3H).

1-bromo-5-ethoxy-4-ethyl-2-methoxybenzene

The title compound was prepared according to the general procedure Hstarting from 2-bromo-4-ethoxy-5-ethylphenol (950 mg, 3.876 mmol). 860 g(86%) of the title compound were prepared. ¹H-NMR (300 MHz, CDCl₃) δ:7.00 (s, 1H), 6.75 (s, 1H), 3.97 (q, J=6.3 Hz, 2H), 3.85 (s, 3H) 2.60(q, J=6.2 Hz, 2H), 1.39 (t, J=6.3 Hz, 3H), 1.18 (t, J=6.2 Hz, 3H).

3-(5-ethoxy-4-ethyl-2-methoxyphenyl)pyridine

The title compound was prepared according to the general procedure Fstarting from 1-bromo-5-ethoxy-4-ethyl-2-methoxybenzene (860 mg, 3.139mmol). 380 mg (44%) of the title compound were prepared.

¹H-NMR (300 MHz, CDCl3) δ: 8.76 (d, J=1.8 Hz, 1H); 8.53 (dd, J=4.9, 1.7Hz, 1H); 7.86 (ddd, J=7.9, 2.3, 1.6 Hz, 1H); 7.31 (ddd, J=7.9, 4.8, 0.9Hz, 1H); 6.84 (s, 1H); 6.81 (s, 1H); 4.03 (q, J=7.0 Hz, 2H); 3.77 (s,3H); 2.70 (q, J=7.5 Hz, 2H); 1.42 (t, J=7.0 Hz, 3H); 1.25 (t, J=7.5 Hz,3H). MS: m/z 258 [M+H]⁺

(R)-3-(5-ethoxy-4-ethyl-2-methoxyphenyl)piperidine hydrochloride (33)and (S)-3-(5-ethoxy-4-ethyl-2-methoxyphenyl)piperidine hydrochloride(34)

The title compounds was prepared according to the general procedure Lstarting from 3-(5-ethoxy-4-ethyl-2-methoxyphenyl)pyridine. Theenantiomers were transformed to the corresponding ter-butyl carboxylatesusing general procedure K and separated using a Daicel Chiralpak IG250×30 mm, 5 μm; mobile phase: 2% Isopropanol/98% Heptane; elution:isocratic; detection: UV 210 nm; flow rate: 40 mL/min. Enantiomer 1(compound 34): Rt 10.06 min (22 mg, 13%), Enantiomer 2 (compound 33): Rt14.35 min (20 mg, 11%). The carboxylates were liberated as thecorresponding hydrochlorides using general procedure L giving the titlescompounds in quantative yields. ¹H-NMR (400 MHz, MeOD) δ 6.79 (s, 1H),6.77 (s, 1H), 4.00 (q, J=7.0 Hz, 2H), 3.80 (s, 3H), 3.45-3.32 (m, 3H),3.10-2.97 (m, 2H), 2.61 (q, J=7.5 Hz, 2H), 2.10-1.99 (m, 1H), 1.97-1.84(m, 3H), 1.38 (t, J=7.0 Hz, 3H), 1.16 (t, J=7.5 Hz, 3H). ¹³C-NMR (100MHz, MeOD) δ 152.2, 152.2, 134.1, 127.7, 113.7, 112.8, 65.7, 56.5, 49.4,45.2, 35.2, 29.2, 24.4, 24.1, 15.4, 15.0. MS: m/z 264 [M+H]⁺

Synthesis of Compound 35

3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-2-methylpyridine

The title compound was prepared according to the general procedure Fstarting from 1-bromo-2,5-dimethoxy-4-(trifluoromethyl)benzene (500 mg,1.75 mmol). 521 mg (99%) of the title compound were prepared. ¹H-NMR(300 MHz, CDCl3) δ: 8.54 (dd, J=5.0, 1.8 Hz, 1H); 7.47 (dd, J=7.6, 1.8Hz, 1H); 7.20 (ddd, J=7.6, 4.9, 0.7 Hz, 1H); 7.17 (s, 1H); 6.82 (s, 1H);3.87 (s, 3H); 3.76 (s, 3H); 2.38 (s, 3H). MS: m/z 298 [M+H]⁺

3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-2-methylpiperidinehydrochloride (35)

The title compound was prepared according to the general procedure Istarting from3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-2-methylpyridine (515 mg,1.732 mmol). The title compound was purified on preparative HPLC:Xbridge Peptide BEH C18 250×19 mm, 10 μm; mobile phase: H₂O/MeOH+0.1%HCOOH; elution: gradient 30% to 50% MeOH (+0.1% HCOOH), 45 min;detection: UV 210 nm; flow rate: 20 mL/min. yielding a singlediastereomer. Minor fractions were discarded. The product containingfractions were evaporated. Aq. NaHCO₃ (50 mL) and Et₂O (50 mL) wereadded to the residue, Et₂O layer separated, aqueous phase extracted withEt₂O (2×50 mL). Combined organic extracts was dried over anhydrousNa₂SO₄, filtered and evaporated. The residue was taken up in Et₂O andtreated with ethereal HCl (2M, 2 mL). The resulting suspension wascentrifugated. Supernatant was discarded, the solid washed with etherand dried under reduced pressure. 83 mg (14%) of the title compound wereprepared. Relative stereochemistry was not elucidated for the isolateddiastereomer (i.e. either cis or trans). The enantiomers of thediastereomer could not be separated. 1H-NMR (400 MHz, MeOD) δ 7.16 (s,1H), 6.97 (s, 1H), 4.07-3.97 (m, 1H), 3.88 (s, 3H), 3.88 (s, 3H), 3.66(dt, J=13.2, 3.7 Hz, 1H), 3.25-3.18 (m, 2H), 2.31 (qd, J=13.1, J=3.8 Hz,1H), 2.16-2.08 (m, 1H), 1.96-1.84 (m, 1H), 1.82-1.75 (m, 1H), 1.11 (d,J=7.1 Hz, 3H). ¹³C-NMR (100 MHz, MeOD) δ 153.0, 151.7, 134.8, 124.9 (q,J=271.5 Hz, 118.9 (q, J=31.1 Hz), 114.3, 110.2 (q, J=5.4 Hz), 57.2,56.6, 51.3, 38.9, 38.4, 24.0, 21.7, 10.3. MS: m/z 304 [M+H]⁺.

Synthesis of Compound 36

3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-5-methylpyridine

The title compound was prepared according to the general procedure Fstarting from 1-bromo-2,5-dimethoxy-4-(trifluoromethyl)benzene (500 mg,1.75 mmol). 308 mg (59%) of the title compound were prepared. ¹H-NMR(300 MHz, CDCl3) S: 8.55 (s, 1H); 8.44 (s, 1H); 7.66 (s, 1H); 7.19 (s,1H); 6.95 (s, 1H); 3.90 (s, 3H); 3.80 (s, 3H); 2.41 (s, 3H). MS: m/z 298[M+H]⁺

cis or trans3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-5-methylpiperidinehydrochloride (36)

The title compound was prepared according to the general procedure Lstarting from3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-5-methylpyridine. Thediastereomers were transformed to the corresponding ter-butylcarboxylates using general procedure K and separated using a DaicelChiralpak IG 250×30 mm, 5 μm; mobile phase: 2% Isopropanol/98% Heptane;elution: isocratic; detection: UV 210 nm; flow rate: 40 mL/min. A singlediastereomer was isolated. Diastereomer 1: Rt 19.07 min (17 mg, 11%).The carboxylate was liberated as the corresponding hydrochloride usinggeneral procedure L giving the title compound in quantitative yields.Relative stereochemistry was not elucidated for the isolateddiastereomer (i.e. either cis or trans). The enantiomers of thediastereomer could not be separated. ¹H-NMR (400 MHz, MeOD) δ: 7.16 (s,1H), 7.07 (s, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.52 (tt, J=12.4, 3.5 Hz,1H), 3.44-3.34 (m, 2H), 3.06 (t, J=12.3 Hz, 1H), 2.70 (t, J=12.3 Hz,1H), 2.09-1.95 (m, 2H), 1.64 (q, J=12.4 Hz, 1H), 1.08 (d, J=6.6 Hz, 3H).¹³C-NMR (100 MHz, MeOD) δ: 153.2, 151.7, 135.3, 124.9 (q, J=271.5 Hz),118.8 (q, J=31.0 Hz), 113.6, 110.6 (q, J=5.4 Hz), 57.1, 56.7, 50.7,48.2, 37.4, 35.1, 30.6, 18.9. MS: m/z 304 [M+H]⁺.

Synthesis of Compounds 37 and 38

5-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-2-methylpyridine

The title compound was prepared according to the general procedure Fstarting from 1-bromo-2,5-dimethoxy-4-(trifluoromethyl)benzene (500 mg,1.75 mmol). 335 mg (64%) of the title compound were prepared. ¹H-NMR(300 MHz, CDCl3) S: 8.64 (dd, J=2.3, 0.8 Hz, 1H), 7.76 (dd, J=8.0, 2.3Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.18 (s, 1H), 6.96 (s, 1H), 3.90 (s,3H), 3.80 (s, 3H), 2.62 (s, 3H). MS: m/z 298 [M+H]⁺

5-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-2-methylpiperidine

The title compound was prepared according to the general procedure Istarting from5-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-2-methylpyridine (335 mg,1.127 mmol). 315 mg (92%) of the title compound were prepared. MS: m/z304 [M+H]⁺

Cis and trans5-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-2-methylpiperidinehydrochloride

Boc protection was performed according to the general procedure Kstarting from5-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-2-methylpiperidine (181 mg,0.597 mmol). 213 mg (88%) of the protected title compound were prepared.The Boc-protected diastereomers were separated on Daicel Chiralpak IF250×30 mm, 5 μm; mobile phase: 2% Isopropanol/98% Heptane; elution:isocratic; detection: UV 210 nm; flow rate: 40 mL/min. Two fractionswere isolated. Boc-Diasteromer 1: Rt 8.89 (69 mg, 31%) andBoc-Diasteromer 2: Rt 16.99 (65 mg, 30%). Boc-diastereomer 1 wasdeprotected according to the general procedure L starting fromtert-butyl5-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-2-methylpiperidine-1-carboxylate(Boc-diastereomer 1, 69 mg, 0.171 mmol). 32 mg (55%) of the titlecompound were prepared. Relative stereochemistry was not furtherelucidated. ¹H-NMR (400 MHz, MeOD) δ 7.16 (s, 1H), 7.11 (s, 1H), 3.90(s, 3H), 3.88 (s, 3H), 3.82-3.75 (m, 1H), 3.44-3.35 (m, 2H), 3.27-3.18(m, 1H), 2.24-2.05 (m, 2H), 1.95-1.92 (m, 1H), 1.85-1.78 (m, 1H), 1.50(d, J=7.0 Hz, 3H). ¹³C-NMR (100 MHz, MeOD) δ 153.2, 151.8, 135.4, 124.9(q, J=271.5 Hz), 118.8 (q, J=31.0 Hz), 114.1, 110.59 (q, J=5.4 Hz),57.2, 56.6, 49.2, 42.6, 36.2, 28.9, 23.2, 14.6. MS: m/z 304 [M+H]⁺Boc-diastereomer 2 was deprotected according to the general procedure Lstarting from tert-butyl5-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-2-methylpiperidine-1-carboxylate(Boc-Diastereomer 2, 65 mg, 0.161 mmol). 27 mg (50%) of the titlecompound were prepared. Relative stereochemistry was not furtherelucidated for the isolated diastereomer. ¹H-NMR (400 MHz, MeOD) δ 8.72(s, 1H), 8.67 (s, 1H), 5.46 (s, 3H), 5.44 (s, 3H), 5.38-5.30 (m, 1H),5.01-4.90 (m, 2H), 4.83-4.73 (m, 1H), 3.80-3.60 (m, 2H), 3.51-3.44 (m,1H), 3.41-3.34 (m, 1H), 3.06 (d, J=7.0 Hz, 3H). ¹³C-NMR (100 MHz, MeOD)δ 153.2, 151.8, 135.4, 124.9 (q, J=271.5 Hz), 118.90 (q, J=31.1 Hz),114.1, 110.6 (q, J=5.4 Hz), 57.2, 56.6, 49.2, 42.6, 36.2, 28.9, 23.2,14.6. MS: m/z 304 [M+H]⁺.

Synthesis of Compounds 39

1-bromo-2-(fluoromethoxy)-5-methoxy-4-(trifluoromethyl)benzene

A flame dried, round-bottom flask, equipped with a stir bar, backfilledwith argon gas, was charged with2-bromo-4-methoxy-5-(trifluoromethyl)phenol (700 mg, 2.583 mmol) and dryMeCN (4 mL). Cs₂CO₃ (1.262 g, 3.874 mmol) was added and the flask wastightly sealed before addition of ICH₂F (0.186 mL, 2.767 mmol) throughthe septum using a syringe. The resulting mixture was stirred overnightat ambient temperature. Upon completion the reaction mixture was pouredinto H₂O (20 mL) and extracted into Et₂O (3×20 mL). The combined organicextracts were dried over Na₂SO₄, filtered and evaporated. The residuewas purified by flash-column chromatography using a mobile phase ofPetroleum ether/EtOAc. 604 mg (77%) of the title compound were prepared.¹H-NMR (300 MHz, CDCl₃) δ: 7.40 (s, 1H), 7.22 (s, 1H), 5.67 (d, J=54.1Hz, 2H), 3.89 (s, 3H).

3-(2-(fluoromethoxy)-5-methoxy-4-(trifluoromethyl)phenyl)pyridine

The title compound was prepared according to the general procedure Fstarting from1-bromo-2-(fluoromethoxy)-5-methoxy-4-(trifluoromethyl)benzene (604 mg,1.993 mmol). 517 mg (86%) of the title compound were prepared. ¹H-NMR(300 MHz, CDCl3) δ: 8.74 (s, 1H); 8.64 (s, 1H); 7.86 (dt, J=7.9, 1.9 Hz,1H); 7.48 (s, 1H); 7.40 (dd, J=7.9, 4.8 Hz, 1H); 6.98 (s, 1H); 5.58 (d,J=54.2 Hz, 2H); 3.93 (s, 3H). MS: m/z 302 [M+H]⁺

(S)-3-(2-(fluoromethoxy)-5-methoxy-4-(trifluoromethyl)phenyl)piperidine(39)

The title compounds was prepared according to the general procedure Lstarting from from3-(2-(fluoromethoxy)-5-methoxy-4-(trifluoromethyl)phenyl)pyridine. Theenantiomers were transformed to the corresponding tert-butylcarboxylates using general procedure K and separated using a DaicelChiralpak IG 250×30 mm, 5 μm; mobile phase: 2% Isopropanol/98% Heptane;elution: isocratic; detection: UV 210 nm; flow rate: 40 mL/min. Only asingle enantiomer was isolated. Enantiomer 1: Rt 16.17 min (30 mg, 33%).The carboxylate was liberated as the corresponding hydrochlorides usinggeneral procedure L giving the title compound in quantitative yield.¹H-NMR (400 MHz, MeOD) δ 7.40 (s, 1H), 7.14 (s, 1H), 5.78 (d, J=54.3 Hz,2H), 3.93 (s, 3H), 3.59-3.39 (m, 3H), 3.25-3.03 (m, 2H), 2.13-1.88 (m,4H). ¹³C-NMR (100 MHz, MeOD, one signal overlapping with CD₃OD) δ 155.3,148.6, 137.9, 124.5 (q, J=271.6 Hz), 119.3 (q, J=31.5 Hz), 116.2 (q,J=5.2 Hz), 113.1, 103.4, (d, J=218.3 Hz), 57.1, 45.1, 35.1, 29.1, 23.9.MS: m/z 308 [M+H]⁺.

Synthesis of Compounds 40 and 41

1-bromo-2,5-diethoxy-4-ethylbenzene

The title compound was prepared according to the general procedure Jstarting from 2-bromo-5-ethyl-4-ethoxyphenol (930 mg, 3.794 mmol). 407mg (39%) of the title compound were prepared. ¹H-NMR (300 MHz, CDCl₃) δ:6.99 (s, 1H), 6.75 (s, 1H), 4.10-3.90 (m, 4H), 2.58 (q, J=7.5 Hz, 2H),1.47-1.32 (m, 6H), 1.17 (t, J=7.5 Hz, 3H).

3-(2,5-diethoxy-4-ethylphenyl)pyridine

The title compound was prepared according to the general procedure Fstarting from 1-bromo-2,5-diethoxy-4-ethylbenzene (407 mg, 1.490 mmol).287 mg (71%) of the title compound were prepared. ¹H-NMR (300 MHz,CDCl₃) δ: 8.81-8.76 (m, 1H); 8.55-8.49 (m, 1H); 7.90 (ddd, J=8.0, 2.3,1.7 Hz, 1H); 7.32 (ddd, J=7.8, 4.8, 0.8 Hz, 1H); 6.84 (s, 1H); 6.81 (s,1H); 4.03 (q, J=7.0 Hz, 2H); 3.97 (q, J=6.9 Hz, 2H); 2.68 (q, J=7.5 Hz,2H); 1.41 (t, J=7.0 Hz, 3H); 1.36-1.21 (m, 6H). MS: m/z 272 [M+H]⁺

(R)-3-(2,5-diethoxy-4-ethylphenyl)piperidine hydrochloride (40) and(R)-3-(2,5-diethoxy-4-ethylphenyl)piperidine hydrochloride (41)

The title compound was prepared according to the general procedure Lstarting from 3-(2,5-diethoxy-4-ethylphenyl)pyridine. The enantiomerswere transformed to the corresponding ter-butyl carboxylates usinggeneral procedure K and separated using a Daicel Chiralpak IC 250×30 mm,5 μm; mobile phase: 2% Isopropanol/98% Heptane; elution: isocratic;detection: UV 210 nm; flow rate: 40 mL/min. Enantiomer 1 (compound 41):Rt 8.04 min (49 mg, 31%), Enantiomer 2 (compound 40): Rt 10.06 min (30mg, 18%). The carboxylates were liberated as the correspondinghydrochlorides using general procedure L giving the titles compounds inquantative yields. ¹H-NMR (400 MHz, MeOD) δ 6.78 (s, 1H), 6.76 (s, 1H),4.06-3.97 (m, 4H), 3.43-3.36 (m, 3H), 3.10-2.98 (m, 2H), 2.59 (q, J=7.5Hz, 2H), 2.07-2.05 (m, 1H), 1.94-1.85 (m, 3H), 1.39 (dt, J=12.4, 7.0 Hz,6H), 1.15 (t, J=7.5 Hz, 3H). ¹³C-NMR (100 MHz, MeOD; one signaloverlapping with CD₃OD) δ 152.3, 151.5, 134.1, 127.9, 114.9, 112.6,65.7, 65.5, 45.2, 35.3, 29.2, 24.4, 24.1, 15.4, 15.0. MS: m/z 278 [M+H]⁺

Synthesis of Compounds 42 and 43

1-bromo-2-ethoxy-4-ethyl-5-methoxybenzene

The title compound was prepared according to the general procedure Jstarting from 2-bromo-5-ethyl-4-methoxyphenol (1.00 g, 4.327 mmol). 813mg (72%) of the title compound were prepared. ¹H-NMR (300 MHz, CDCl₃) δ:7.00 (s, 1H), 6.76 (s, 1H), 4.05 (q, J=6.4 Hz, 2H), 3.78 (s, 3H), 2.57(q, J=6.1 Hz, 2H), 1.43 (t, J=6.4 Hz, 3H), 1.16 (q, J=6.1 Hz, 3H).

3-(2-ethoxy-4-ethyl-5-methoxyphenyl)pyridine

The title compound was prepared according to the general procedure Fstarting from 1-bromo-2-ethoxy-4-ethyl-5-methoxybenzene (813 mg, 3.134mmol). 543 mg (67%) of the title compound were prepared.

¹H-NMR (300 MHz, CDCl3) δ: 8.80 (s, 1H); 8.53 (d, J=4.1 Hz, 1H); 7.91(dt, J=7.9, 1.8 Hz, 1H); 7.33 (dd, J=7.9, 4.8 Hz, 1H); 6.85 (s, 1H);6.82 (s, 1H); 3.98 (q, J=7.0 Hz, 2H); 3.83 (s, 3H); 2.67 (q, J=7.5 Hz,2H); 1.30 (t, J=7.0 Hz, 3H); 1.23 (t, J=7.5 Hz, 3H). MS: m/z 258 [M+H]⁺.

(R)-3-(2-ethoxy-4-ethyl-5-methoxyphenyl)piperidine (42) and(S)-3-(2-ethoxy-4-ethyl-5-methoxyphenyl)piperidine (43)

The title compounds was prepared according to the general procedure Lstarting from 3-(2-ethoxy-4-ethyl-5-methoxyphenyl)pyridine. Theenantiomers were transformed to the corresponding tert-butylcarboxylates using general procedure K and separated using a DaicelChiralpak IC 250×30 mm, 5 μm; mobile phase: 2% Isopropanol/98% Heptane;elution: isocratic; detection: UV 210 nm; flow rate: 40 mL/min.Enantiomer 1 (compound 43): Rt 8.99 min (50 mg, 34%), Enantiomer 2(compound 42): Rt 11.48 min (49 mg, 36%). The carboxylates wereliberated as the corresponding hydrochlorides using general procedure Lgiving the titles compounds in quantitative yields. ¹H-NMR (300 MHz,MeOD) δ 6.81 (s, 1H), 6.79 (s, 1H), 4.05 (q, J=7.0, 2H), 3.81 (s, 3H),3.46-3.36 (m, 3H), 3.14-3.00 (m, 2H), 2.60 (q, J=7.5, 2H), 2.12-2.06 (m,1H), 1.99-1.89 (m, 3H), 1.43 (t, J=7.0, 3H), 1.16 (t, J=7.5, 3H).¹³C-NMR (100 MHz, MeOD; one signal overlapping with CD₃OD) δ 153.0,151.5, 133.7, 128.0, 115.0, 111.2, 66.5, 56.6, 45.2, 35.3, 29.2, 24.3,24.1, 15.4, 15.0. MS: m/z 264 [M+H]⁺.

Synthesis of Compounds 44 and 45

2-bromo-4-fluoro-5-(trifluoromethyl)phenol

The title compound was prepared according to the general procedure Gstarting from commercially available 4-fluoro-3-(trifluoromethyl)phenol(8.00 g, 44.420 mmol. 5.15 g (45%) of the title compound were prepared.¹H-NMR (400 MHz, CDCl₃) δ: 7.36 (d, J=6.0 Hz, 1H), 7.24 (d, J=6.0 Hz,1H). MS: m/z 260 [M+H]⁺.

1-bromo-5-fluoro-2-methoxy-4-(trifluoromethyl)benzene

The title compound was prepared according to the general procedure Hstarting from 2-bromo-4-fluoro-5-(trifluoromethyl)phenol (8.67 g, 33.483mmol). 6.10 g (67%) of the title compound were prepared. ¹H-NMR (400MHz, CDCl₃) δ: 7.45 (d, J=8.0 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 3.92 (s,3H). MS: m/z 274 [M+H]⁺

3-(5-fluoro-2-methoxy-4-(trifluoromethyl)phenyl)pyridine

The title compound was prepared according to the general procedure Fstarting from 1-bromo-5-fluoro-2-methoxy-4-(trifluoromethyl)benzene(2.00 g, 7.325 mmol). 1.51 g (76%) of the title compound were prepared.¹H-NMR (300 MHz, CDCl3) a: 8.75 (d, J=2.2 Hz, 1H); 8.62 (d, J=4.6 Hz,1H); 7.84 (dt, J=7.9, 1.9 Hz, 1H); 7.37 (dd, J=7.9, 4.9 Hz, 1H); 7.19(d, J=10.3 Hz, 1H); 7.14 (d, J=5.7 Hz, 1H); 3.85 (s, 3H). MS: m/z 272[M+H]⁺

3-(2-methoxy-5-(methylthio)-4-(trifluoromethyl)phenyl)pyridine

The title compound was prepared according to the general Procedure 0starting from 3-(5-fluoro-2-methoxy-4-(trifluoromethyl)phenyl)pyridine.(700 mg, 2.581 mmol) 515 mg (67%) of the title compound were prepared.¹H-NMR (300 MHz, CDCl3) δ 8.76 (s, 1H), 8.62 (s, 1H), 7.86 (dt, J=7.9,1.9 Hz, 1H), 7.42 (s, 1H), 7.38 (dd, J=7.7, 4.9 Hz, 1H), 7.27 (s, 1H),3.86 (s, 3H), 2.50 (s, 3H). MS: m/z 300 [M+H]⁺

(R)-3-(2-methoxy-5-(methylthio)-4-(trifluoromethyl)phenyl)piperidinehydrochloride (44) and(S)-3-(2-methoxy-5-(methylthio)-4-(trifluoromethyl)phenyl)piperidinehydrochloride (45)

The title compounds were prepared according to the general procedure Lstarting 3-(2-methoxy-5-(methylthio)-4-(trifluoromethyl)phenyl)pyridine.The enantiomers were transformed to the corresponding tert-butylcarboxylates using general procedure K and separated using a on DaicelChiralpak IF 250×30 mm, 5 μm; mobile phase: 2% Isopropanol/98% Heptane;elution: isocratic; detection: UV 210 nm; flow rate: 40 mL/min.Enantiomer 1 (compound 45): Rt 7.94 min (90 mg, 14%), Enantiomer 2(compound 44): Rt 9.71 min (88 mg, 14%). The carboxylates were liberatedas the corresponding hydrochlorides using general procedure L giving thetitles compounds in quantative yields. ¹H-NMR (400 MHz, MeOD) δ 7.46 (s,1H), 7.26 (s, 1H), 3.92 (s, 3H), 3.51-3.42 (m, 3H), 3.18-3.04 (m, 2H),2.50 (s, 3H), 2.11-2.06 (m, 1H), 2.00-1.89 (m, 3H). ¹³C-NMR (100 MHz,MeOD; one signal overlapping with CD₃OD) δ 156.7, 134.8, 131.8, 130.8(q, J=30.4 Hz), 130.1, 125.1 (q, J=273.1 Hz), 110.4 (q, J=6.0 Hz), 56.5,45.2, 35.2, 28.7, 24.0, 18.4. MS: m/z 306 [M+H]⁺.

Synthesis of Compounds 46 and 47

3-(2-methoxy-5-(ethylthio)-4-(trifluoromethyl)phenyl)pyridine

The title compound was prepared according to the general procedure 0starting from 3-(5-fluoro-2-methoxy-4-(trifluoromethyl)phenyl)pyridine(700 mg, 2.581 mmol). 460 mg (57%) of the title compound were prepared.¹H-NMR (300 MHz, CDCl3) δ 8.75 (dd, J=2.3, 0.9 Hz, 1H), 8.61 (dd, J=4.8,1.7 Hz, 1H), 7.84 (ddd, J=7.9, 2.3, 1.7 Hz, 1H), 7.51 (d, J=0.9 Hz, 1H),7.37 (ddd, J=7.9, 4.9, 0.9 Hz, 1H), 7.28 (s, 1H), 3.87 (s, 3H), 2.93 (q,J=7.4 Hz, 2H), 1.29 (t, J=7.4 Hz, 3H). MS: m/z 314 [M+H]⁺.

(R)-3-(2-methoxy-5-(ethylthio)-4-(trifluoromethyl)phenyl)piperidinehydrochloride (46) and(S—3-(2-methoxy-5-(ethylthio)-4-(trifluoromethyl)phenyl)piperidinehydrochloride (47)

The title compounds were prepared according to the general procedure Lstarting from3-(2-methoxy-5-(ethylthio)-4-(trifluoromethyl)phenyl)pyridine. Theenantiomers were transformed to the corresponding tert-butylcarboxylates using general procedure K and separated using a DaicelChiralpak IG 250×30 mm, 5 μm; mobile phase: 2% Isopropanol/98% Heptane;elution: isocratic; detection: UV 210 nm; flow rate: 40 mL/min.Enantiomer 1 (compound 47): Rt 9.59 min (90 mg, 9%), Enantiomer 2(compound 46): Rt 11.09 min (98 mg, 10). The carboxylates were liberatedas the corresponding hydrochlorides using general procedure L giving thetitle compounds in quantitative yields. ¹H-NMR (400 MHz, MeOD) δ 7.46(s, 1H), 7.20 (s, 1H), 3.86 (s, 3H), 3.44-3.36 (m, 3H), 3.10-2.98 (m,2H), 2.88 (q, J=7.3 Hz, 2H), 2.03-2.01 (m, 1H), 1.92-1.84 (m, 3H), 1.17(t, J=7.3 Hz, 3H). ¹³C-NMR (100 MHz, MeOD; one signal overlapping withCD₃OD) δ 157.2, 134.6, 134.5, 132.6 (q, J=29.9 Hz), 127.8, 125.0 (q,J=273.0 Hz), 110.3 (q, J=5.8 Hz), 56.5, 45.1, 35.0, 30.8, 28.8, 23.9,14.6. MS: m/z 320 [M+H]⁺.

Synthesis of Compounds 48 and 49

3-(3-methoxy-4-(trifluoromethyl)phenyl)pyridine

The title compound was prepared according to the general procedure Fstarting from 4-bromo-2-methoxy-1-(trifluoromethyl)benzene (500 mg, 1.96mmol). 391 mg (79%) of the title compound were prepared. ¹H-NMR (300MHz, CDCl3) S: 8.86 (s, 1H); 8.66 (d, J=4.7 Hz, 1H); 7.90 (d, J=7.9 Hz,1H); 7.67 (d, J=8.0 Hz, 1H); 7.43 (dd, J=7.9, 4.8 Hz, 1H); 7.20 (d,J=8.1 Hz, 1H); 7.16 (s, 1H); 3.99 (s, 3H). MS: m/z 254 [M+H]⁺.

(R)-3-(3-methoxy-4-(trifluoromethyl)phenyl)piperidine hydrochloride (48)and (S)-3-(3-methoxy-4-(trifluoromethyl)phenyl)piperidine hydrochloride(49)

The title compounds were prepared according to the general procedure Istarting from 3-(3-methoxy-4-(trifluoromethyl)phenyl)piperidine. Theenantiomers were transformed to the corresponding tert-butylcarboxylates using general procedure K. and separated using a DaicelChiralpak IF 250×30 mm, 5 μm; mobile phase: 2% Isopropanol/98% Heptane;elution: isocratic; detection: UV 210 nm; flow rate: 40 mL/min.Enantiomer 1 (compound 49): Rt 10.15 min (131 mg, 49%), Enantiomer 2(compound 48): Rt 13.22 min (122 mg, 45%). The carboxylates wereliberated as the corresponding hydrochlorides using general procedure Lgiving the titles compounds in quantitative yields. ¹H-NMR (400 MHz,MeOD) δ 7.54 (d, J=8.0 Hz, 1H), 7.13 (s, 1H), 7.00 (d, J=8.0 Hz, 1H),3.93 (s, 3H), 3.47-3.43 (m, 2H), 3.19 (t, J=12.1 Hz, 1H), 3.15-3.07 (m,2H), 2.11-2.06 (m, 2H), 1.99-1.82 (m, 2H). ¹³C-NMR (100 MHz, MeOD; onesignal overlapping with CD₃OD) δ 159.3, 148.9, 128.4 (q, J=5.3 Hz),125.1 (q, J=271.3 Hz), 119.7, 118.8 (q, J=31.1 Hz), 112.5, 56.6, 45.0,41.6, 30.6, 23.8. MS: m/z 260 [M+H]⁺

Synthesis of Compounds 50 and 51

(R)-3-(5-fluoro-2-methoxy-4-(trifluoromethyl)phenyl)piperidinehydrochloride (50) and(5)-3-(5-fluoro-2-methoxy-4-(trifluoromethyl)phenyl)piperidinehydrochloride (51)

The title compounds was prepared according to the general procedure Lstarting from3-(5-fluoro-2-methoxy-4-(trifluoromethyl)phenyl)piperidine. Theenantiomers were transformed to the corresponding tert-butylcarboxylates using general procedure K and separated using a DaicelChiralpak IC 250×30 mm, 5 μm; mobile phase: 2% Isopropanol/98% Heptane;elution: isocratic; detection: UV 210 nm; flow rate: 40 mL/min.Enantiomer 1 (compound 51): Rt 9.38 min (36 mg, 23% mg), Enantiomer 2(compound 50): Rt 18.16 min (38, 20%). The carboxylates were liberatedas the corresponding hydrochlorides using general procedure L giving thetitles compounds in quantitative yields. 1H-NMR (400 MHz, MeOD) δ 7.29(d, J=11.2 Hz, 1H), 7.21 (d, J=5.8 Hz, 1H), 3.92 (s, 3H), 3.54-3.43 (m,3H), 3.10-3.01 (m, 2H), 2.11-2.07 (m, 1H), 2.04-1.81 (m, 3H). ¹³C-NMR(100 MHz, MeOD; one signal overlapping with CD₃OD) δ 155.2 (d, J=247.6Hz), 154.5, 137.0 (d, J=7.4 Hz), 124.0 (q, J=271.3 Hz), 118.0 (td,J=33.1, 13.5 Hz), 117.3 (d, J=23.6 Hz), 109.7 (d, J=5.1 Hz), 56.9, 45.1,34.9, 28.7, 23.8. MS: m/z 278 [M+H]⁺.

Synthesis of Compounds 52 and 53

3-(2-methoxy-4-(trifluoromethyl)phenyl)pyridine

The title compound was prepared according to the general procedure Fstarting from 1-bromo-2-methoxy-4-(trifluoromethyl)benzene (500 mg,1.960 mmol). 392 mg (79%) of the title compound were prepared. MS: m/z254 [M+H]⁺

(R)-3-(2-methoxy-4-(trifluoromethyl)phenyl)piperidine hydrochloride (52)and (S)-3-(2-methoxy-4-(trifluoromethyl)phenyl)piperidine hydrochloride(53)

The title compounds were prepared according to the general procedure Istarting from 3-(2-methoxy-4-(trifluoromethyl)phenyl)pyridine. Theenantiomers were transformed to the corresponding tert-butylcarboxylates using general procedure K and separated using a DaicelChiralpak IG 250×30 mm, 5 μm; mobile phase: 5% Isopropanol/95% Heptane;elution: isocratic; detection: UV 210 nm; flow rate: 40 mL/min.Enantiomer 1 (compound 53): Rt 9.11 min (22 mg, 31%), Enantiomer 2(compound 52): Rt 10.31 min (19 mg, 32%). The carboxylates wereliberated as the corresponding hydrochlorides using general procedure Lgiving the titles compounds in quantitative yields. ¹H-NMR (400 MHz,MeOD) δ 7.44 (d, J=7.9 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.24 (s, 1H),3.94 (s, 3H), 3.54-3.42 (m, 3H), 3.12-3.02 (m, 2H), 2.12-2.05 (m, 1H),2.01-1.88 (m, 3H). ¹³C-NMR (100 MHz, MeOD; one signal overlapping withCD₃OD) δ 158.7, 134.5, 131.8 (q, J=32.3 Hz), 128.9, 125.5 (q, J=271.4Hz), 118.7 (q, J=4.0 Hz), 108.5 (q, J=3.7 Hz), 56.4, 45.2, 35.0, 28.9,24.0. MS: m/z 260 [M+H]⁺

Synthesis of Compounds 54 and 551-bromo-2-cyclopropoxy-5-methoxy-4-(trifluoromethyl)benzene

A flame dried microwave vial, backfilled with argon, was charged with2-bromo-4-methoxy-5-(trifluoromethyl)phenol (1.00 g, 3.690 mmol), Cs₂CO₃(3.606 g, 11.069 mmol), NaI (55 mg, 0.369 mmol, 0.1 eq),bromocyclopropane (1.178 mL, 1.785 g, 14.758 mmol) and dry DMF (6 mL).The reaction was heated for 10 h at 150° C. Upon completion the reactionwas allowed to cool to ambient temperature and poured into sat. aq.NH₄Cl and extracted with EtOAc (3×20 mL). The combined organic extractswere dried over Na₂SO₄, filtered, and evaporated. The residue waspurified by flash-column chromatography with the Petroleum ether/EtOAcmobile phase. 590 mg (51%) of the title compound were prepared ¹H-NMR(300 MHz, CDCl₃) δ 7.43 (s, 1H), 7.20 (s, 1H), 3.86 (s, 3H), 3.83-3.75(m, 1H), 0.86-0.81 (m, 4H).

tert-butyl5-(2-cyclopropoxy-5-methoxy-4-(trifluoromethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

A flame dried microwave vial, backfilled with argon gas, was chargedwith tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(1.173 g, 3.793 mmol), Pd(dppf)Cl₂*DCM (77 mg, 0.095 mmol, 5 mol %),K₂CO₃ (524 mg, 3.793 mmol) and1-bromo-2-cyclopropoxy-5-methoxy-4-(trifluoromethyl)benzene (590 mg,1.896 mmol) in the glove box and tightly sealed. Degassed H₂O (3.5 mL)and dioxane (7 mL) was added and the resulting mixture was heated usingmicrowave irradiation at 100° C. for 16 h, then cooled to ambienttemperature. The reaction mixture was filtered through a silica pad,further eluted with EtOAc and evaporated in vacuo. The residue waspurified by reversed-phase flash-column chromatography with H₂O/MeOHmobile phase. 735 mg (89%) of the title compound were prepared. ¹H-NMR(300 MHz, CDCl₃) δ 7.40 (s, 1H), 6.81 (s, 1H), 5.94-5.83 (m, 1H), 4.13(br s, 2H), 3.87 (s, 3H), 3.76-3.68 (m, 1H), 3.55 (t, J=5.8 Hz, 2H),2.34-2.25 (m, 2H), 1.48 (s, 9H), 0.82-0.72 (m, 4H). MS: m/z 414 [M+H]⁺

tert-butyl3-(2-cyclopropoxy-5-methoxy-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate

A round-bottom flask, equipped with a stir bar was charged withtert-butyl5-(2-cyclopropoxy-5-methoxy-4-(trifluoromethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate(230 mg, 0.556 mmol, 1 eq) and EtOH (7 mL) then 10% Pd/C (59 mg, 0.056mmol, 10 mol %) was added. The flask was evacuated and backfilled withH₂ 8 times, then stirred for 16 h under H₂ atmosphere. Upon completionthe catalyst was filtered off and volatiles evaporated in vacuo. Theresidue was purified on prep. HPLC: Xbridge Peptide BEH C18 250×19 mm,10 μm; mobile phase: H₂O/MeCN+0.1% AcOH; elution: gradient 20% to 80%MeCN (+0.1% AcOH), 1 h; detection: UV 210 nm; flow rate: 20 mL/min.¹H-NMR (300 MHz, CDCl₃) δ 7.40 (s, 1H), 6.82 (s, 1H), 4.22-3.98 (m, 2H),3.86 (s, 3H), 3.78-3.68 (m, 1H), 3.07-2.94 (m, 1H), 2.86-2.63 (m, 2H),1.97-1.86 (m, 1H), 1.79-1.52 (m, 3H), 1.46 (s, 9H), 0.87-0.69 (m, 4H).MS: m/z 416 [M+H]⁺

(R)-3-(2-cyclopropoxy-5-methoxy-4-(trifluoromethyl)phenyl)piperidinehydrochloride (54) and(S)-3-(2-cyclopropoxy-5-methoxy-4-(trifluoromethyl)phenyl)piperidinehydrochloride (55)

The title compound was prepared according to the general procedure Lstarting from tert-butyl3-(2-cyclopropoxy-5-methoxy-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate.The enantiomers were separated using a Daicel Chiralpak IF 250×30 mm, 5μm; mobile phase: 2% Isopropanol/98% Heptane; elution: isocratic;detection: UV 210 nm; flow rate: 40 mL/min. Compound 55: Rt 7.74 min (35mg, 53%). Compound 54: Rt 9.85 min (36 mg, 53%). The carboxylates wereliberated as the corresponding hydrochlorides using general procedure Lgiving the titles compounds in quantitative yields. ¹H-NMR (400 MHz,MeOD) δ 7.49 (s, 1H), 7.07 (s, 1H), 3.88 (s, 3H), 3.87-3.82 (m, 1H),3.47-3.34 (m, 3H), 3.17-3.00 (m, 2H), 2.12-2.02 (m, 1H), 1.99-1.83 (m,3H), 0.88-0.72 (m, 4H). ¹³C NMR (100 MHz, MeOD) δ 153.4, 150.9, 135.3,124.9 (q, J=271.6 Hz), 118.8 (q, J=31.0 Hz), 113.5, 112.4 (q, J=5.3 Hz),57.2, 52.5, 48.7, 45.2, 35.3, 28.8, 23.9, 6.8. MS: m/z 316 [M+H]⁺

Synthesis of Compounds 56 and 57

2-bromo-5-butyl-4-methoxyphenol

The title compound was prepared according to the general procedure Gstarting from known 3-butyl-4-methoxyphenol (1.15 g, 6.380 mmol) 934 mg(56%) of the title compound were prepared. ¹H-NMR (400 MHz, CDCl₃) δ6.88 (s, 1H), 6.82 (s, 1H), 3.76 (s, 3H), 2.53 (t, J=10.0 Hz, 2H),1.58-1.47 (m, 2H), 1.34 (dd, J=15.1, 7.3 Hz, 2H), 0.91 (t, J=8.0 Hz,3H).

1-bromo-4-butyl-2,5-dimethoxybenzene

The title compound was prepared according to the general procedure Hstarting from 2-bromo-5-butyl-4-methoxyphenol (934 mg, 3.604 mmol). 343g (35%) of the title compound were prepared. ¹H-NMR (300 MHz, CDCl₃) δ7.01 (s, 1H), 6.73 (s, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 2.59-2.53 (m,2H), 1.59-1.49 (m, 2H), 1.36 (dd, J=15.3, 7.2 Hz, 2H), 0.93 (t, J=7.3Hz, 3H).

3-(4-butyl-2,5-dimethoxyphenyl)pyridine

The title compound was prepared according to the general procedure Fstarting from 1-bromo-4-butyl-2,5-dimethoxybenzene (340 mg, 1.245 mmol).308 mg (91%) of the title compound were prepared. ¹H-NMR (300 MHz,CDCl3) δ: 8.78 (s, 1H); 8.54 (d, J=4.0 Hz, 1H); 7.92 (d, J=7.9 Hz, 1H);7.36 (dd, J=7.9, 4.9 Hz, 1H); 6.82 (s, 1H); 6.81 (s, 1H); 3.82 (s, 3H);3.77 (s, 3H); 2.69-2.60 (m, 2H); 1.67-1.54 (m, 2H); 1.48-1.33 (m, 2H);0.96 (t, J=7.3 Hz, 3H). MS: m/z 272[M+H]⁺

(R)-3-(4-butyl-2,5-dimethoxyphenyl)piperidine hydrochloride (56) and(S)-3-(4-butyl-2,5-dimethoxyphenyl)piperidine hydrochloride (57)

The title compound was prepared according to the general procedure Lstarting from tert-butyl3-(4-butyl-2,5-dimethoxyphenyl)piperidine-1-carboxylate. The enantiomerswere transformed to the corresponding tert-butyl carboxylates usinggeneral procedure K and separated using a Daicel Chiralpak IF 250×30 mm,5 μm; mobile phase: 2% Isopropanol/98% Heptane; elution: isocratic;detection: UV 210 nm; flow rate: 40 mL/min. Enantiomer 1: Rt 8.08 min(90, 48% mg), Enantiomer 2: Rt 11.15 min (100 mg, 52%). The carboxylateswere liberated as the corresponding hydrochlorides using generalprocedure L. giving the titles compounds in quantitative yields. ¹H-NMR(400 MHz, MeOD) δ 6.78 (s, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 3.45-3.34(m, 3H), 3.10-2.99 (m, 2H), 2.60-2.55 (m, 2H), 2.10-2.04 (m, 1H),1.97-1.85 (m, 3H), 1.57-1.49 (m, 2H), 1.38-1.29 (m, 2H), 0.93 (t, J=7.3Hz, 3H). ¹³C-NMR (100 MHz, MeOD) δ 153.1, 152.0, 132.3, 127.7, 114.4,111.3, 56.6, 56.5, 45.2, 35.2, 33.5, 30.9, 24.1, 23.6, 14.3. MS: m/z 278[M+H]⁺.

(R)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-1-ethylpiperidine (58)

The title compound was prepared according to the general procedure Mstarting from 3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidinehydrochloride Enantiomer 2 (60 mg, 0.184 mmol) and acetaldehyde. 54 mg(92%) of the title compound were prepared. ¹H-NMR (400 MHz, MeOD) δ 7.16(s, 1H), 7.10 (s, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.68-3.52 (m, 3H),3.23 (q, J=7.3 Hz, 2H), 3.17 (t, J=12.3 Hz, 1H), 3.01 (t, J=12.5 Hz,1H), 2.19-2.10 (m, 1H), 2.05-1.88 (m, 3H), 1.38 (t, J=7.3 Hz, 3H).¹³C-NMR (100 MHz, MeOD) δ 153.2, 151.7, 135.2, 124.9 (q, J=271.6 Hz),118.9 (q, J=31.1 Hz), 113.8, 110.7 (q, J=5.3 Hz), 57.2, 56.8, 56.6,53.7, 53.2, 36.0, 28.6, 24.5, 9.6. MS (m/z): 318 [M+H]⁺.

(S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-1-ethylpiperidine (59)

The title compound was prepared according to the general procedure Mstarting from 3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidinehydrochloride Enantiomer 1 (60 mg, 0.184 mmol) and acetaldehyde. 57 mg(97%) of the title compound were prepared. ¹H-NMR (400 MHz, MeOD) δ 7.16(s, 1H), 7.10 (s, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.67-3.52 (m, 3H),3.23 (q, J=7.3 Hz, 2H), 3.16 (t, J=12.4 Hz, 1H), 3.01 (t, J=12.4 Hz,1H), 2.19-2.10 (m, 1H), 2.04-1.89 (m, 3H), 1.38 (t, J=7.3 Hz, 3H).¹³C-NMR (100 MHz, MeOD) δ 153.2, 151.7, 135.1, 124.9 (q, J=271.5 Hz),118.9 (q, J=31.1 Hz), 113.8, 110.7 (q, J=5.3 Hz), 57.2, 56.8, 56.6,53.7, 53.2, 36.0, 28.6, 24.5, 9.6. MS (m/z): 318 [M+H]⁺.

(R)3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-1-methylpiperidine (60)

The title compound was prepare according to the genera procedure MStarting from 3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidinehydrochloride Enantiomer 2 (34 mg, 0.104 mmol) and formalin, 27 mg (85%)of the title compound were prepared. 1H-NMR (400 MHz, MeOD) δ 7.17 (s,1H), 7.07 (s, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.61-3.47 (m, 3H), 3.20(t, J=12.8 Hz, 1H), 3.06 (t, J=12.3 Hz, 1H), 2.92 (s, 3H), 2.18-2.08 (m,1H), 2.02-1.83 (m, 3H). ¹³C-NMR (100 MHz, MeOD) δ 153.2, 151.7, 135.0,124.9 (q, J=271.7 Hz), 119.0 (q, J=31.1 Hz), 113.7, 110.6 (q, J=5.5 Hz),58.7, 57.2, 56.7, 55.6, 44.3, 36.2, 28.0, 24.7. MS (m/z): 304 [M+H]⁺.

(S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-1-methylpiperidine (61)

The title compound was prepared according to the general procedure MStarting from 3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidinehydrochloride Enantiomer 1 (40 mg, 0.123 mmol) and formalin, 35 mg (94%)of the title compound were prepared. ¹H-NMR (400 MHz, MeOD) δ 7.17 (s,1H), 7.08 (s, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.62-3.47 (m, 3H), 3.21(t, J=12.6 Hz, 1H), 3.06 (t, J=12.0 Hz, 1H), 2.92 (s, 3H), 2.18-2.08 (m,1H), 2.03-1.83 (m, 3H). ¹³C-NMR (100 MHz, MeOD) δ 153.2, 151.7, 135.0,124.9 (q, J=271.5 Hz), 119.0 (q, J=31.0 Hz), 113.7, 110.7 (q, J=5.3 Hz),58.7, 57.2, 56.7, 55.5, 44.3, 36.2, 28.1, 24.7. MS (m/z): 304 [M+H]⁺.

Enantiomer Identity Elucidation

To elucidate the absolute stereochemistry of the separated enantiomers,an x-ray crystal structure of 59 and 58 was generated as example.Compound 59 (the fastest eluting enantiomer) was determined to be the(S)-enantiomer and compound 58 (the slowest eluting enantiomer) wasdetermined to be the (R)-enantiomer. The stereochemistry of theremaining compounds was assigned based on order of elution (i.e. initialor secondary elution based on retention time).

Preparation of XRD Analysis Suitable Crystals Using Hydrochloride Salts

The substrate (20-40 mg) was dissolved in EtOAc/chloroform (1:1)(3-4 mL)in an 10 mL vial. The vial was sealed with a screw-cap with a rubberseptum insert. Samples were allowed to evaporate over 72 h until theformation of prismatic crystals was observed.

Generation of the X-Ray Structure of Compounds 58 and 59

A suitable crystal 0.18×0.13×0.11 mm3 was selected and mounted on asuitable support and analysed using a Rigaku, XtaLAB Synergy, Dualflex,HyPix diffractometer. The crystal was kept at a steady T=150.0(1) Kduring data collection. The structure was solved with the help of ShelXTstructure solution program¹⁷ using the Intrinsic Phasing solutionmethod. The model was refined with version of the program olex2. refineusing Gauss-Newton minimisation¹⁸

Embodiments of the Invention (Items)

1. A 5-HT_(2A) agonist of the general formula (III)

or a pharmaceutically acceptable salt thereof wherein:

X is selected from the group consisting of I, CN, S—(C₁-C₅ alkyl),S—(C₁-C₅ fluoroalkyl), S—(C₂-C₅ alkenyl), S—(C₂-C₅ fluoroalkenyl),S—(C₂-C₅ alkynyl), S—(C₂-C₅ fluoroalkynyl), C₂-C₅ alkyl, C₁-C₅fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅ fluoroalkenyl, C₂-C₅ alkynyl and C₂-C₅fluoroalkynyl;

Y¹ and Y² are independently selected from the group consisting of H, O,S, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and halogen;

R¹ is not present when Y is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

R² is not present when Y² is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen;

when present, R¹ and R² are independently selected from the groupconsisting of C₁-C₅ alkyl, C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅fluoroalkenyl, C₂-C₅ alkynyl, C₂-C₅ fluoroalkynyl, C₃-C₅ cycloalkyl, andC₃-C₅ fluorocycloalkyl;

* denotes the (R) or (S) stereoisomer or any mixture thereof if a chiralcenter is present;

n is an integer with a value of 1, 2, 3 or 4 to form an azetidine,pyrrolidine, piperidine or azepane ring system;

z denotes the number of R³ groups and is an integer with a value of 0,1, 2, 3 or 4 each R³ is independently selected from the group consistingof F, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₂-C₃ alkenyl, and C₂-C₃ alkynyl;

R⁴ is H or CH₃;

with the proviso that at least one of Y¹ or Y² is selected as O or S.

2. A 5-HT_(2A)/5-HT_(2C) agonist according to item 1, wherein n is aninteger with a value of 1, 2, 3 or 4 to 25 form an azetidine,pyrrolidine, piperidine or azepane ring system with the proviso thatwhen n=3,* denotes the (R) stereoisomer.

3. A selective 5-HT_(2A) agonist according to item 1, wherein n is aninteger with a value 3 to form a piperidine and (*) denotes the (5)stereoisomer of the general formula (II)

4. A 5-HT_(2A) agonist according to any of the preceding items, whereinX is selected from the group consisting of I, CN, S—CH₃, S—CF₃, C₂-C₃alkyl, C₁-C₃ fluoroalkyl, ethynyl, fluoroethynyl, and cyclopropyl, R¹and R² are independently selected from the group consisting of C₁-C₃alkyl, C₁-C₃ fluoroalkyl, and C₃-C₅ cycloalkyl; z is 0, 1, 2, or 3; andeach R³ is independently selected from F, C₁-C₂ alkyl, and C₁-C₂fluoroalkyl.

5. A 5-HT_(2A) agonist according to any of the preceding items, whereinX is selected from the group consisting of I, CN, S—CH₃, S—CF₃, C₂-C₃alkyl, and C₁-C₃ fluoroalkyl.

6. A 5-HT_(2A) agonist according to any of the preceding items, whereinX is selected from the group consisting of I, CN, S—CH₃, S—CF₃, C₂-C₃alkyl, and C₁-C₂ fluoroalkyl.

7. A 5-HT_(2A) agonist according to any of the preceding items, whereinX is selected from the group consisting of I, CN, S—CH₃, S—CF₃, ethyl,and CF₃.

8. A 5-HT_(2A) agonist according to any of the preceding items, whereinX is selected from the group consisting of I, CN, and CF₃.

9. A 5-HT_(2A) agonist according to any of the preceding items, whereinX is CF₃.

10. A 5-HT_(2A) agonist according to any of the preceding items, whereinY¹ and Y² are independently selected from the group consisting of O, S,C₁-C₂ alkyl, and C₁-C₂ fluoroalkyl.

11. A 5-HT_(2A) agonist according to any of the preceding items, whereinY¹ and Y² are independently selected from the group consisting of O, S,CH₃, and CF₃.

12. A 5-HT_(2A) agonist according to any of the preceding items, whereinY¹ and Y² are independently selected from the group consisting of O,CH₃, and CF₃.

13. A 5-HT_(2A) agonist according to any of the preceding items, whereinY¹ and Y² are independently selected from the group consisting of 0 andCH₃.

14. A 5-HT_(2A) agonist according to any of the preceding items, whereinR¹ and R² are independently selected from the group consisting of notpresent (deleted), C₁-C₃ alkyl, and C₁-C₃ fluoroalkyl.

15. A 5-HT_(2A) agonist according to any of the preceding items, whereinR¹ and R² are independently selected from the group consisting of C₁-C₃alkyl, C₁-C₃ and fluoroalkyl, and wherein Y¹ and Y² are O.

16. A 5-HT_(2A) agonist according to any of the preceding items, whereinz is 0, 1, 2 or 3.

17. A 5-HT_(2A) agonist according to any of the preceding items, whereinz is 0, 1 or 2.

18. A 5-HT_(2A) agonist according to any of the preceding items, whereinz is 0 or 1.

19. A 5-HT_(2A) agonist according to any of the preceding items, whereinz is 0.

20. A 5-HT_(2A) agonist according to any of the preceding items 1-18,wherein z is 1, 2, 3, or 4, and each R³ is independently selected fromthe group consisting of F, CH₃, and CF₃.

21. A 5-HT_(2A) agonist according to any of the preceding items 1-18,wherein z is 1, 2, 3, or 4, and each R³ is independently selected from Fand CH₃.

22. A 5-HT_(2A) agonist according to any of the preceding items 1-18,wherein z is 1, 2, 3, or 4, and each R³ is CH₃.

23. A 5-HT_(2A) agonist according to any of the preceding items, with a5-HT_(2A) EC₅₀ value below 100 nM when measured in the Ca²⁺/Fluo-4assay.

24. A method of treating a depressive disorder, comprising:

-   -   Administering an effective amount of a medicament comprising a        compound of general formula (III) or a pharmaceutically        acceptable salt thereof to a subject in need thereof;

Wherein general formula (III) has the structure, (II),

wherein:

X is selected from the group consisting of F, Cl, Br, I, CN, S—(C₁-C₅alkyl), S—(C₁-C₅ fluoroalkyl), S—(C₂-C₅ alkenyl), S—(C₂-C₅fluoroalkenyl), S—(C₂-C₅ alkynyl), S—(C₂-C₅ fluoroalkynyl), C₁-C₅ alkyl,C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅ fluoroalkenyl, C₂-C₅ alkynyl,and C₂-C₅ fluoroalkynyl;

Y¹ and Y² are independently selected from the group consisting of H, O,S, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and halogen;

R¹ is not present when Y is H, C₁-C₃, alkyl, C₁-C₃ fluoroalkyl orhalogen;

R² is not present when Y² is H, C₁-C₃, alkyl, C₁-C₃ fluoroalkyl orhalogen;

when present, R¹ and R² are independently selected from the groupconsisting of C₁-C₅ alkyl, C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅fluoroalkenyl, C₂-C₅ alkynyl, C₂-C₅ fluoroalkynyl, C₃-C₅ cycloalkyl, andC₃-C₅ fluorocycloalkyl;

* denotes the (R) or (S) stereoisomer or any mixture thereof if a chiralcenter is present;

n is an integer with a value of 1, 2, 3 or 4 to form an azetidine,pyrrolidine, piperidine or azepane ring system;

z denotes the number of R³ groups and is an integer with a value of 0,1, 2, 3 or 4 each R³ is independently selected from the group consistingof F, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₂-C₃ alkenyl, and C₂-C₃ alkynyl;

R⁴ is H or CH₃;

with the proviso that at least one of Y¹ or Y² is selected as O or S.

25. A method according to item 24, wherein n is an integer with a valueof 1, 2 or 4 to form an azetidine, pyrrolidine or azepane ring system.

26. A method according to item 24, wherein n is an integer with a value3 to form a piperidine and (*) denotes the (5) stereoisomer of thegeneral formula (II)

27. A method according to any of the items 24-26, wherein X is selectedfrom the group consisting of F, Cl, Br, I, CN, S—CH₃, S—CF₃, C₁-C₃alkyl, C₁-C₃ fluoroalkyl, ethynyl, fluoroethynyl, and cyclopropyl; R¹and R² are independently selected from the group consisting of C₁-C₃alkyl, C₁-C₃ fluoroalkyl, and C₃-C₅ cycloalkyl; z is 0, 1 or 2; and eachR³ is independently selected from the group consisting of F, C₁-C₂alkyl, and C₁-C₂ fluoroalkyl.

28. A method according to any of the items 24-27, wherein X is selectedfrom the group consisting of F, Cl, Br, I, CF₃, CN, S—CH₃, S—CF₃, C₁-C₃alkyl, and C₂-C₃ fluoroalkyl.

29. A method according to any of the items 24-28, wherein X is selectedfrom the group consisting of F, Cl, Br, I, CN, S—CH₃, S—CF₃, C₂-C₃alkyl, and C₁-C₂ fluoroalkyl.

30. A method according to any of the items 24-29, wherein X is selectedfrom the group consisting of Br, I, CN, S—CH₃, S—CF₃, CH₃, and CF₃.

31. A method according to any of the items 24-30, wherein X is selectedfrom the group consisting of Br, I, and CF₃.

32. A method according to any of the items 24-31, wherein X is CF₃.

33. A method according to any of the items 24-32, wherein Y¹ and Y² areindependently selected from the group consisting of O, S, C₁-C₂ alkyl,and C₁-C₂ fluoroalkyl.

34. A method according to any of the items 24-33, wherein Y¹ and Y² areindependently selected from the group consisting of O, S, CH₃, and CF₃.

35. A method according to any of the items 24-34, wherein Y¹ and Y² areindependently selected from the group consisting of O, CH₃, and CF₃.

36. A method according to any of the items 24-35, wherein Y¹ and Y² areindependently selected from the group consisting of 0 and CH₃.

37. A method according to any of the items 24-36, wherein R¹ and R² areindependently either not present or selected from the group consistingof C₁-C₃ alkyl, and C₁-C₃ fluoroalkyl.

38. A method according to any of the items 24-37, wherein R¹ and R² areindependently selected from the group consisting of C₁-C₃ alkyl, andC₁-C₃ fluoroalkyl; and wherein Y¹ and Y² are O.

39. A method according to any of the items 24-38, wherein z is 0, 1, 2or 3.

40. A method according to any of the items 24-39, wherein z is 0, 1 or2.

41. A method according to any of the items 24-40, wherein z is 0 or 1.

42. A method according to any of the items 24-41, wherein z is 0.

43. A method according to any of the items 24-41, wherein z is 1, 2, 3,or 4, and each R³ is independently selected from the group consisting ofF, CH₃, and CF₃.

44. A method according to any of the items 24-41, wherein z is 1, 2, 3,or 4, and each R³ is independently selected from the group consisting ofF and CH₃.

45. A method according to any of the items 24-41, wherein z is 1, 2, 3,or 4, and R³ is CH₃.

46. A method according to any of the items 24-41, wherein the compoundof general formula (III) or general formula (II) has a 5-HT_(2A) EC₅₀value below 100 nM when measured in the Ca²⁺/Fluo-4 assay.

47. A method according to any of the items 24-46, in the treatment ofdepressive disorder.

48. A method according to any of the items 24-47, wherein the depressivedisorder is MDD.

49. A method according to any of the items 24-48, wherein the depressivedisorder is treatment-resistant depression.

50. A method according to any of the items 24-49, wherein the medicamentis administered at a regular interval in a dose range of 0.1 mg to 500mg.

51. A method according to any of the items 24-50, the regular intervalis selected from the group consisting of daily, weekly, biweekly, andmonthly.

52. A pharmaceutical composition comprising a compound according to anyof the preceding items, a pharmaceutical acceptable carrier andoptionally one or more excipients.

1. A compound of the general formula (I) or a pharmaceuticallyacceptable salt thereof

wherein: * denotes the (R) or (S) stereoisomer or any mixture thereof; Xis selected from the group consisting of I, CN, S—(C₁-C₅ alkyl),S—(C₁-C₅ fluoroalkyl), S—(C₂-C₅ alkenyl), S—(C₂-C₅ fluoroalkenyl),S—(C₂-C₅ alkynyl), S—(C₂-C₅ fluoroalkynyl), C₂-C₅ alkyl, C₁-C₅fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅ fluoroalkenyl, C₂-C₅ alkynyl, andC₂-C₅ fluoroalkynyl; Y¹ and Y² are independently selected from the groupconsisting of H, O, S, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and halogen; R¹is not present when Y is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, or halogen;R² is not present when Y² is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, orhalogen; when present, R¹ and R² are independently selected from thegroup consisting of C₁-C₅ alkyl, C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅fluoroalkenyl, C₂-C₅ alkynyl, C₂-C₅ fluoroalkynyl, C₃-C₅ cycloalkyl, andC₃-C₅ fluorocycloalkyl; z denotes the number of R³ groups and is aninteger with a value of 0, 1, 2, or 3; each R³ is independently selectedfrom the group consisting of F, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₂-C₃alkenyl, and C₁-C₃ alkynyl; and R⁴ is H or CH₃; with the proviso that atleast one of Y¹ or Y² is selected as O or S.
 2. The compound accordingto claim 1, wherein X is selected from I, CN, S—(C₁-C₃ alkyl), S—(C₁-C₃fluoroalkyl), C₂-C₄ alkyl, C₁-C₄ fluoroalkyl, ethynyl, fluoroethynyl orcyclopropyl.
 3. The compound according to claim 1, wherein X is selectedfrom I, CN, S—(C₁-C₃ alkyl), S—(C₁-C₃ fluoroalkyl), C₂-C₄ alkyl or C₁-C₄fluoroalkyl;
 4. The compound according to claim 1, wherein Y¹ and Y² areindependently selected from the group consisting of H, O, S, halogen,and CH₃.
 5. The compound according to claim 1, wherein Y¹ and Y² areindependently selected from the group consisting of O, S, and H.
 6. Thecompound according to claim 1, wherein Y¹ and Y² are independentlyselected from O or S.
 7. The compound according to claim 1, wherein R¹and R² are independently not present or are independently selected fromthe group consisting of C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and C₃-C₅cycloalkyl.
 8. The compound according to claim 1, wherein R¹ and R² areindependently selected from the group consisting of C₁-C₂ alkyl, C₁-C₂fluoroalkyl and cyclopropyl.
 9. The compound according to claim 1,wherein z is 0 or 1, and R³ is selected from the group consisting of F,C₁-C₂ alkyl, and C₁-C₂ fluoroalkyl.
 10. The compound according to claim1, wherein z is 0 or 1, and each R³ is selected from the groupconsisting of F, CH₃, and CF₃.
 11. The compound according to claim 1,wherein * denotes (S) and R⁴ is H.
 12. The compound according to claim1, wherein the one or more R³ groups are present at position 2, 3 or 6in the piperidine.
 13. A method of treating a depressive disorder,comprising: administering an effective amount of a medicament comprisinga compound of the general formula (I) or a pharmaceutically acceptablesalt thereof to a subject in need thereof; wherein general formula (I)has the structure,

wherein: * denotes the (R) or (S) stereoisomer or any mixture thereof; Xis selected from the group consisting of F, Cl, Br, I, CN, S—(C₁-C₅alkyl), S—(C₁-C₅ fluoroalkyl), S—(C₂-C₅ alkenyl), S—(C₂-C₅fluoroalkenyl), S—(C₂-C₅ alkynyl), S—(C₂-C₅ fluoroalkynyl), C₁-C₅ alkyl,C₁-C₅ fluoroalkyl, C₂-C₅ alkenyl, C₂-C₅ fluoroalkenyl, C₂-C₅ alkynyl,and C₂-C₅ fluoroalkynyl; Y¹ and Y² are independently selected from thegroup consisting of H, O, S, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, andhalogen; R¹ is not present when Y is H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl,or halogen; R² is not present when Y² is H, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, or halogen; when present, R¹ and R² are independentlyselected from the group consisting of C₁-C₅ alkyl, C₁-C₅ fluoroalkyl,C₂-C₅ alkenyl, C₂-C₅ fluoroalkenyl, C₂-C₅ alkynyl, C₂-C₅ fluoroalkynyl,C₃-C₅ cycloalkyl, and C₃-C₅ fluorocycloalkyl; z denotes the number of R³groups and is an integer with a value of 0, 1, 2, or 3; each R³ isindependently selected from the group consisting of F, C₁-C₃ alkyl,C₁-C₃ fluoroalkyl, C₂-C₃ alkenyl, and C₁-C₃ alkynyl; and R⁴ is H or CH₃;with the proviso that at least one of Y¹ or Y² is selected as O or S.14. The method of claim 13, wherein X is selected from the groupconsisting of F, Cl, Br, I, CN, S—(C₁-C₃ alkyl), S—(C₁-C₃ fluoroalkyl),C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, ethynyl, fluoroethynyl, and cyclopropyl;15. The method of claim 13, wherein X is selected from the groupconsisting of F, Cl, Br, I, CN, S—(C₁-C₃ alkyl), S—(C₁-C₃ fluoroalkyl),C₁-C₄ alkyl, and C₁-C₄ fluoroalkyl;
 16. The method of claim 13, whereinY¹ and Y² are independently selected from the group consisting of H, O,S, halogen, and CH₃.
 17. The method of claim 13, wherein Y¹ and Y² areindependently selected from the group consisting of O, S, and H.
 18. Themethod of claim 13, wherein Y¹ and Y² are independently selected from Oor S.
 19. The method of claim 13, wherein R¹ and R² are independentlynot present or are independently selected from the group consisting ofC₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and C₃-C₅ cycloalkyl.
 20. The method ofclaim 13, wherein R¹ and R² are selected from the group consisting ofC₁-C₂ alkyl, C₁-C₂ fluoroalkyl and cyclopropyl.
 21. The method of claim13, wherein z is 0 or 1, and R³ is selected from the group consisting ofF, C₁-C₂ alkyl, and C₁-C₂ fluoroalkyl.
 22. The method of claim 13,wherein z is 0 or 1, and each R³ is independently selected from thegroup consisting of F, CH₃, and CF₃.
 23. The method of claim 13,wherein * denotes (S) and R⁴ is H.
 24. The method of claim 13, whereinthe one or more R³ groups are present at position 2, 3 or 6 in thepiperidine.
 25. The method of claim 13, wherein the of general formula(I) or a pharmaceutically acceptable salt thereof is administered inorder to treat a depressive disorder selected from a list consisting ofmajor depressive disorder (MDD) (also known as clinical depression,unipolar depression), melancholia, psychotic depression, antenataldepression, postnatal depression, bipolar disorder, bipolar type Idisorder, bipolar type II disorder, cyclothymic disorder, dysthymicdisorder or seasonal affective disorder, treatment-resistant depressiondisorder (TRD), and severe treatment-resistant depression disorder. 26.The method of claim 13, wherein the medicament further comprises apharmaceutical acceptable carrier, optionally one or more excipients,and optionally other therapeutically active ingredients.
 27. The methodof claim 14, wherein the medicament is administered at a regularinterval in a dose range of 0.1 mg to 500 mg.